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Endocrine Reviews 25(6):9711010 Copyright 2004 by The Endocrine Society doi: 10.1210/er.2003-0018

From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines
BIEKE F. SCHRIJVERS, AN S. DE VRIESE,
AND

ALLAN FLYVBJERG

Medical Department M (B.F.S., A.F.), Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University Hospital, DK-8000 Aarhus, Denmark; and Renal Unit (B.F.S., A.S.D.V.), Department of Internal Medicine, Gent University Hospital, B-9000 Gent, Belgium
At present, diabetic kidney disease affects about 1525% of type 1 and 30 40% of type 2 diabetic patients. Several decades of extensive research has elucidated various pathways to be implicated in the development of diabetic kidney disease. This review focuses on the metabolic factors beyond blood glucose that are involved in the pathogenesis of diabetic kidney disease, i.e., advanced glycation end-products and the aldose reductase system. Furthermore, the contribution of hemodynamic factors, the renin-angiotensin system, the endothelin system, and the nitric oxide system, as well as the prominent role of the intracellular signaling molecule protein kinase C are discussed. Finally, the respective roles of TGF-, GH and IGFs, vascular endothelial growth factor, and plateletderived growth factor are covered. The complex interplay between these different pathways will be highlighted. A brief introduction to each system and description of its expression in the normal kidney is followed by in vitro, experimental, and clinical evidence addressing the role of the system in diabetic kidney disease. Finally, well-known and potential therapeutic strategies targeting each system are discussed, ending with an overall conclusion. (Endocrine Reviews 25: 9711010, 2004)

I. Introduction II. Metabolic Factors A. Advanced glycation endproducts (AGEs) B. Aldose reductase (AR) /polyol pathway III. Hemodynamic Factors A. Angiotensin II (Ang II)/renin-angiotensin system (RAS) B. Endothelin (ET) C. Nitric oxide (NO) IV. Intracellular Factors A. Diacylglycerol (DAG)-protein kinase C (PKC) pathway V. Growth Factors and Cytokines A. Transforming growth factor (TGF-) B. Growth hormone (GH) and insulin-like growth factors (IGFs) C. Vascular endothelial growth factor (VEGF) D. Platelet-derived growth factor (PDGF) VI. Outlook and Future Perspectives
Abbreviations: ACE, Angiotensin-converting enzyme; ACEi, ACE inhibitor(s); ADMA, asymmetric dimethylarginine; AGE, advanced glycation endproduct; AGE-R, AGE receptor; AGE-R3, AGE-R type 3, galectin-3; AKR, aldo-keto reductase(s); Ang, angiotensin; AR, aldose reductase; ARB, Ang receptor blocker; ARI, AR inhibitor; AS-ODN, antisense oligodeoxynucleotide; AT1, Ang II type 1 receptor; BB, BioBreeding; bFGF, basic fibroblast growth factor; BMT, basement membrane thickness; cGMP, cyclic GMP; CML, carboxymethyl lysine; CrCl, creatinine clearance; CTGF, connective tissue growth factor; DAG, diacylglycerol; DDAH, dimethylarginine-dimethylaminohydrolase; ECE, ET-converting enzyme; ECM, extracellular matrix; EM, electron microscopic; ET, endothelin; ETA, ET receptor A; ETB, ET receptor B; GFR, glomerular filtration rate; GHBP, GH binding protein; GHR, GH receptor; I/D polymorphism, insertion/deletion polymorphism; IGFBP, IGF binding protein; IGFBP-rP, IGFBP-related proteins; IGF-II/man-6-PR,

I. Introduction

IABETIC NEPHROPATHY IS one of the most serious complications of diabetes and the most common cause of end-stage renal failure in the Western world. At present, diabetic kidney disease affects about 15 to 25% of type 1 diabetic patients (1) and 30 to 40% of patients with type 2 diabetes (2, 3). Diabetic nephropathy is characterized by specific renal morphological and functional alterations. Features of early diabetic renal changes are glomerular hyperfiltration, glomerular and renal hypertrophy, increased urinary albumin excretion (UAE), increased basement membrane thickness (BMT), and mesangial expansion with the accumulation of extracellular matrix (ECM) proteins such as collagen, fibronectin, and laminin. Advanced diabetic ne-

IGF-II/mannose-6-phosphate receptor; IGF-IR, IGF-I receptor; l-NAME, Ng-nitro-l-arginine methyl ester; l-NMMA, NG-monomethyl-l-arginine; L-NNA, N--nitro-l-arginine; MMP, matrix metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NF-B, nuclear factor-B; NO, nitric oxide; NOD, nonobese diabetic; NOS, NO synthase; NOS1/nNOS, neuronal NO synthase; NOS2/iNOS, inducible NO synthase; NOS3/eNOS, endothelial NOS; NOx, NO2 and NO3; OLETF, Otsuka-Long-Evans-Tokushima-fatty; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PKC, protein kinase C; PM, pyridoxamine dihydrochloride; PTB, N-phenacetylthiazolium bromide; RAGE, receptor for AGEs; RAS, renin-angiotensin system; RPF, renal plasma flow; ScR-II, macrophage scavenger receptor type II; SDH, sorbitol dehydrogenase; SNP, single nucleotide polymorphism; SOD, superoxide dismutase; SPARC, secreted protein acidic and rich in cysteine; STZ, streptozotocin; TGF- RI, TGF- receptor type I; TKi, tyrosine kinase inhibitor(s); TZD, thiazolidinedione; UAE, urinary albumin excretion; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell; ZDF, Zucker diabetic fatty. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.

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phropathy is characterized by proteinuria, a decline in renal function, decreasing creatinine clearance (CrCl), glomerulosclerosis, and interstitial fibrosis. As will appear from this review, a vast majority of the studies referenced have been performed in diabetic animals. This raises the question whether diabetic rodents are good models of human disease. The most frequently used animal strain in experimental diabetes is the rat. In spontaneous and chemically [e.g., streptozotocin (STZ)] induced rat models of type 1 diabetes, as well as rat models of type 2 diabetes, early renal changes are seen: renal enlargement, glomerular hypertrophy, hyperfiltration, and an increasing UAE (4, 5). Furthermore, diabetic rats with a diabetes duration of more than 6 months develop electron microscopic (EM) changes, i.e., increased BMT (6 8). Over the past years, diabetic mice models have been used more frequently in the study of diabetic renal changes. As is the case for rats, diabetic mice present with early renal changes comparable with the changes seen in diabetic rats, i.e., renal enlargement, glomerular hypertrophy, hyperfiltration, and a progressive increase in UAE (9). In contrast to diabetic rats, diabetic mice models develop pronounced structural glomerular EM changes after approximately 2 months duration of diabetes with an increase in BMT and mesangial expansion (9, 10). In conclusion, various diabetic rodent models display early renal changes that have similarities to the early changes seen in human diabetes, whereas only diabetic mice present with increased BMT and mesangial expansion at an EM-level within a diabetes duration of a few months. Over the past few decades, extensive research has elucidated several pathways that play a role in the development and/or progression of diabetic kidney disease. Beyond the role of high blood glucose, the pathophysiological role of different metabolic pathways in the development and progression of diabetic nephropathy has been studied extensively. Advanced glycation endproduct (AGE) formation as a consequence of sustained or transient hyperglycemia has been implicated. Furthermore, the potential role of the aldose reductase/polyol pathway, although controversial, will be addressed. In addition, various vasoactive factors contribute to the development and progression of diabetic microvascular complications. These vasoactive factors include vasoconstrictors such as angiotensin (Ang) II and endothelin (ET), as well as vasodilators such as nitric oxide (NO). Besides the well-known systemic and locally hemodynamic effects, the renin-angiotensin system (RAS) and the ET system can exert nonhemodynamic effects via an autocrine or paracrine mode of action. They stimulate the proliferation of kidney cells and the expression of growth factors or cytokines, which may directly or indirectly contribute to the renal changes seen in diabetes. The controversial role of the NO system in renal hemodynamic changes in diabetes will also be addressed. Activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is also a well-known feature of diabetes. PKC is an important intracellular pathway that can be activated by many of the metabolic and hemodynamic factors involved in the pathogenesis of diabetic nephropathy. PKC can then be a stimulus for the initiation of several growth factors and cytokines.

Different growth factors and cytokines directly influence kidney function or exert their effects in a more indirect way by stimulating other factors. One of the first endocrine factors to be implicated in the pathogenesis of diabetes was GH (11). The attention was drawn to the possible role of GH in the development of diabetic microangiopathy (12). At about the same time, IGFs were identified in diabetic serum (13). Since then, new information has appeared with increasing pace on growth factors implicated in the pathogenesis of the renal functional and structural alterations seen in diabetes. Ample experimental and clinical studies illustrate the prominent role of TGF-, and during the last several years an increasing interest has developed in vascular endothelial growth factor (VEGF). Although platelet-derived growth factor (PDGF) has been studied less intensively, evidence supporting its pathophysiological role in diabetic kidney disease has been collected.

II. Metabolic Factors A. Advanced glycation endproducts (AGEs)

1. The AGE system. When glucose and other reactive carbonyl compounds react nonenzymatically with proteins, lipids, or nucleic acids, Schiff bases and Amadori products are formed. Additional rearrangement and modification leads to the generation of diverse AGEs, such as carboxymethyl lysine (CML), pentosidine, imidazolone, and pyrraline (14, 15). AGEs interact with specific receptors (14 16). p60 (OST-48, AGE-R1), p90 (80K-H, AGE-R2), galectin-3 (AGE-R3), the macrophage scavenger receptor type II (ScR-II), and CD36 regulate the uptake and clearance of AGEs (14, 16). The best-characterized receptor is receptor for AGEs (RAGE) (14). Another molecule with AGE-binding and anti-AGE properties is the antimicrobial protein lysozyme (16). AGEs can also act in a receptor-independent way by cross-linking proteins (14, 15). AGEs alter the structure and function of intra- and extracellular molecules, increase oxidative stress, and modulate cell activation, signal transduction, and the expression of cytokines and growth factors through receptor-dependent and receptor-independent pathways (14 16). 2. Expression of AGEs in the normal kidney. In human kidney, immunostaining for pentosidine, pyrraline, CML, and imidazolone was negative in glomeruli (1719), but in renal tubuli, immunostaining was negative for CML and pentosidine in one study (19) but positive for pentosidine, CML, and imidazolone in others (17, 18). AGE staining was present in rodents, predominantly in endothelial cells within glomeruli and tubulointerstitium (20, 21). AGE and RAGE colocalize in the rat glomerulus (21). In rat kidney, RAGE is expressed in cortex and medulla (22) and localized primarily to glomeruli, distal tubules, and collecting ducts (21). In human kidney, a low level of RAGE is constitutively expressed in glomerular podocytes, but not in the mesangium or glomerular endothelium (19). In the mouse kidney, mRNA and protein for AGE-R1, AGE-R2, and AGE-R3 were detected as well as mRNA for RAGE and the ScR-II (23). More particularly, a distinct glomerular AGE-R1 staining was found, and AGE-R1 to -3 were also detected in cultured

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mouse mesangial cells (23). RAGE was detected in cultured mouse podocytes (10). Human-, rat-, and mouse-cultured mesangial cells contain binding sites for AGE-modified proteins (24, 25). AGE binding sites were also identified in proximal tubules of rat kidney, but it is unclear whether they represent one of the known AGE receptors (26). 3. In vitro evidence for AGEs effects on renal cells. In cultured glomerular endothelial and mesangial cells, glycated albumin and AGE-rich proteins increased PKC activity (2729), PKC (29), TGF-1 levels (27, 30), and ECM expression (24, 25, 27, 29, 30). Hyperglycemia and glycated albumin appeared to exert an additive effect in glomerular endothelial cells (27). In cultured kidney epithelial cells, CML reduced proteoglycan expression (31). In a proximal tubular epithelial cell line, AGEs induced tubular-epithelial myofibroblast transdifferentiation through RAGE signaling (32). 4. Experimental evidence for a role of AGEs in diabetic kidney disease. In vivo evidence for a role of AGEs in diabetic kidney disease comes mainly from studies in STZ-diabetic rats. BSAAGE gold conjugate binding to mesangial matrix, BMT, and glomerular cell nuclei was more intense in renal tissue from diabetic than from control rats (33). Whether this was associated with an up-regulation of RAGE was not investigated. In STZ-diabetic rats, AGE staining was increased in the glomeruli, predominantly in glomerular endothelial cells, and tubulointerstitium (21). Renal AGE levels were increased after 3 (26), 12 (34), and 32 wk of diabetes (20, 35). Furthermore, exogenously administered AGEs induced ECM genes (36), mesangial expansion (37), and up-regulation of TGF-1 in nondiabetic mice and rats (36, 37). Recently, it was demonstrated in nonobese diabetic (NOD) and db/db mice, models of type 1 and type 2 diabetes, respectively, that the intake of food-derived AGEs contributes to diabetic nephropathy and that low AGE diet provides renoprotection (9). An increased number of proximal tubular AGE binding sites was found in type 1 diabetic rats together with an increase in renal AGE levels (26). Recently, in STZ-diabetic rats, RAGE was up-regulated after 4 wk of diabetes up to 12 wk, whereas AGE-R2 and AGE-R3 remained unchanged (22, 34). In NOD mice, early after the onset of diabetes, AGE-R1 expression was reduced, AGE-R2 expression was unchanged, and AGER3, RAGE, and ScR-II expression was increased compared with nondiabetic control mice (23). In db/db mice, glomerular RAGE staining was enhanced, especially in podocytes, compared with nondiabetic control mice (10). Diabetic transgenic mice overexpressing human RAGE developed renal and glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene (38). 5. Clinical evidence for a role of AGEs in diabetic kidney disease. In type 1 diabetic patients, increased circulating AGEs preceded the development of microvascular complications (39) and predicted the progression of the early morphological renal changes in BMT and matrix/glomerular volume fraction (40). In monocytes of type 1 diabetic patients, reduced expression of AGE-R1 was linked to elevated serum AGE levels and the presence of severe diabetic complications (41).

In type 2 diabetic patients, increased serum levels of crossline, one of the structurally defined adducts of AGEs, were associated with the presence of nephropathy (42). In addition, serum concentrations of AGEs were associated with the development of diabetic microangiopathy in patients with type 2 diabetes (43). Amadori products, pentosidine, CML, pyrraline, and imidazolone were demonstrated in renal tissue of diabetic patients (17, 18). CML accumulated predominantly in the basement membrane and pentosidine primarily in the interstitium in patients with diabetic kidney disease (17, 19). The extent of CML and pentosidine immunostaining in the glomerular and tubulointerstitial compartments correlated with the severity of diabetic nephropathy (19). The distinctive pattern of CML accumulation in diabetic nephropathy differed from the more nonspecific AGE accumulation observed in nondiabetic sclerosing renal diseases. Glomeruli of patients with diabetic nephropathy demonstrated diffuse up-regulation of RAGE expression in podocytes (19). 6. Agents with effects on AGEs in diabetic kidney disease. Various classes of drugs are able to interfere with the formation of AGEs or the cross-linking of proteins by AGEs. Aminoguanidine, pyridoxamine, 2,3-diamino-phenazine, OPB-9195, and tenilsetam inhibit AGE formation by scavenging reactive carbonyl intermediates, N-phenacetylthiazolium bromide (PTB) and ALT-711 are AGE-cross-link breakers. Furthermore, signal transduction through RAGE can be inhibited by antisense oligodeoxynucleotides (AS-ODNs), RAGE antibodies, or soluble RAGE. Drugs targeting other systems have also shown some effects on AGE-related pathways. a. Glycated albumin antagonists. Treatment of db/db mice with monoclonal antibodies against Amadori-modified glycated albumin (A717) attenuated the cortical overexpression of 1 (IV) collagen and fibronectin mRNAs, ameliorated mesangial matrix expansion, reduced albuminuria, and prevented the decline in renal function that developed in untreated db/db mice (44, 45). Oral administration of EXO-226 or 23CPPA, compounds that reduce circulating glycated albumin, had similar renoprotective effects in db/db mice (46, 47). The effects of 23CPPA were mediated by a reduction in glomerular TGF-1 (47). b. Inhibitors of AGE formation. Aminoguanidine retarded the development of diabetic nephropathy in long-term experimental diabetes in rats (6, 20, 35, 48). It appears that the renoprotective effects of aminoguanidine in diabetes are related to the duration and not the timing of treatment (20, 49) and are mediated by a decrease of AGE formation (21, 26, 50). In addition, aminoguanidine restored the diabetes-induced changes in lysosomal processing (51) and glomerular PKC activity (49, 52) in STZ-diabetic rats. Recently, in STZ-diabetic transgenic (mREN-2)27 rats, a model of diabetic kidney disease with hypertension and an overactive RAS, aminoguanidine ameliorated glomerulosclerosis and medullary pathology and decreased glomerular AGE immunolabeling, but had no effect on kidney weight, glomerular filtration rate (GFR), or UAE (53). Aminoguanidine had no effect on the expression of RAGE, AGE-R2, and AGE-R3 in STZ-diabetic rats. Compared with placebo, aminoguanidine modestly re-

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duced proteinuria and marginally slowed progression of overt diabetic nephropathy in optimally treated type 1 diabetic patients (54). However, two double-blinded, placebocontrolled randomized clinical trials with aminoguanidine were performed in type 1 (I) and type 2 (II) diabetic patients with overt nephropathy. The primary endpoint, i.e., reducing the risk of doubling serum creatinine, was not achieved in ACTION I, but pimagedine reduced urinary protein excretion, serum triglycerides, and low-density lipoprotein levels. ACTION II was terminated early because of side effects and apparent lack of efficacy (55). Pyridorin (pyridoxamine dihydrochloride) (PM) inhibits the conversion of Amadori intermediates to AGEs in vitro (56). PM inhibited the increase of albuminuria and serum creatinine in STZ-diabetic rats (57). The therapeutic potential of PM is currently being investigated in humans with diabetic nephropathy (15). 2,3Diamino-phenazine inhibited AGE accumulation in vitro (50). In STZ-diabetic rats, 2,3-diamino-phenazine normalized the renal AGE staining (50) and ameliorated collagen solubility, but had no effect on increased UAE (58). OPB-9195 effectively inhibited AGE formation and AGE-derived crosslinking in vitro. In Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes, the administration of OPB-9195 lowered elevated serum AGE levels and UAE, attenuated glomerular AGE deposition, and prevented the progression of glomerulosclerosis (8). Furthermore, administering OPB-9195 in a RAGE transgenic mouse model prevented the features of advanced diabetic nephropathy (38). In vitro, tenilsetam restored the reduced digestibility of collagen, and in vivo, administration of tenilsetam for 16 wk suppressed the elevated levels of AGE-derived fluorescence and pyrraline in renal cortex of STZ-induced diabetic rats (59). c. AGE-receptor blockers. In cultured mesangial cells, antip60 antibodies prevented the AGE-induced increases in IGF-I, TGF-1, and ECM expression or production (60), and anti-p60 and anti-p90 antibodies prevented the AGEinduced increase in type IV collagen (24). In db/db mice treated with a neutralizing murine RAGE antibody for 2 months, the increases in kidney weight, glomerular volume, mesangial volume, and UAE were reduced, and the increases in CrCl and BMT were normalized (Fig. 1) (61). In db/db mice, treatment with soluble RAGE prevented the increases in VEGF and TGF- expression, mesangial expansion, BMT, and UAE and preserved renal function. Similarly, these di-

abetes-induced changes were not seen in diabetic RAGE null mice (10). d. AGE-cross-link breakers. PTB cleaves covalent, glucosederived protein cross-links in vitro and in vivo (62). However, PTB treatment did not affect the elevated UAE or the decreased collagen pepsin solubility in STZ-diabetic rats (58). The lack of effect could be due to the unstable nature of PTB. The stable PTB derivative ALT-711 reduced renal AGE accumulation, TGF- immunostaining, and tubular-epithelial myofibroblast transdifferentiation in STZ-diabetic rats (32). ALT-946 is a potent inhibitor of AGE accumulation and AGEprotein cross-linking (63). Treatment with ALT-946 for 16 to 32 wk attenuated the increases in GFR, albuminuria, and glomerular AGE staining observed in STZ-diabetic rats (63). Recently, in STZ-diabetic (mREN-2)27 rats, treatment with ALT-946 for 12 wk ameliorated glomerulosclerosis and medullary pathology, reduced cortical tubular degeneration, UAE, and glomerular AGE staining, but had no effect on kidney weight or GFR (53). The renoprotective effect of AGEcross-link breakers has not been tested in clinical trials. e. Aldose reductase inhibitors (ARIs). Epalrestat decreased the elevated levels of fructose 3-phosphate and AGEs in erythrocytes after 2 months of treatment (64), supporting the hypothesis that the polyol pathway plays a substantial role in the nonenzymatic glycation of proteins (64, 65). f. Others. In cultured mesangial cells, lysozyme suppressed the AGE-enhanced expression of several modulators of kidney structure and function, i.e., PDGF-B, type 1 (IV) collagen and tenascin, and normalized the AGE-suppressed expression and activity of matrix metalloproteinase-9 (MMP). In vivo, lysozyme administration to NOD and db/db mice reduced the elevated serum AGE levels, enhanced urinary AGE excretion, and decreased UAE (66). PDGF-antibody abrogated the AGE-induced increase in type IV collagen in cultured mesangial cells, indicating that this response was not mediated directly by AGEs and RAGE, but indirectly through an intermediate factor, i.e., PDGF (24). Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors (ACEi) lower the formation of AGEs in vitro by lowering the production of reactive carbonyl precursors (67). Ramipril attenuated the renal AGE accumulation found in STZ-diabetic rats, identifying a relationship between the RAS and the accumulation of AGEs in experimental diabetic nephropathy (34).

FIG. 1. BMT and total mesangial volume on d 60 in placebo-treated db/ mice (open bars), RAGE antibody-treated db/db mice (light gray bars), placebo-treated db/db mice (black bars), and RAGE antibody-treated db/db mice (dark gray bars). Data are means SEM, n 6 10 in each group. *, P 0.01 vs. db/ mice and RAGE antibody-treated db/db mice. , P 0.05 vs. db/ mice and placebo-treated db/db mice. [Reproduced with permission from A. Flyvbjerg et al.: Diabetes 53:166 172, 2004 (61). American Diabetes Association.]

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7. Conclusion. In vitro and experimental data suggest that the up-regulation of AGEs and RAGE, and AGE-RAGE interaction contribute to diabetic renal changes, i.e., TGF-1 upregulation, PKC activation, renal and glomerular hypertrophy, albuminuria, ECM production, mesangial expansion, and glomerulosclerosis. Reduced AGE-R1-dependent clearance may be responsible for increased circulating AGEs that are associated with the development of microvascular complications. AGEs accumulate in the kidney, especially in diabetic lesions. Inhibitors of AGE formation are promising agents because they improve functional and/or structural changes associated with diabetic kidney disease in experimental models. Despite promising preliminary effects in type 1 diabetic patients, aminoguanidine still needs to prove its effect in randomized clinical trials. Although the renoprotective effects of AGE formation inhibitors are mainly mediated through decreased AGE formation, multiple pathways are affected, i.e., cytokines such as TGF-1, IGF-I, PDGF-B, VEGF, PKC activity, and NO synthase (NOS). The renal effects of AGE-receptor blockers, RAGE antibodies, and AGE-cross-link breakers implicate AGE signaling pathways in the functional and structural changes of diabetic kidney disease.
B. Aldose reductase (AR)/polyol pathway

the papilla, in endothelial, epithelial, interstitial and collecting duct cells. In the outer medulla, it was low in proximal tubules and thick limb cells and strong in endothelial, distal tubular, and collecting duct cells (76, 77). Vascular smooth muscle cells (VSMCs) were positive for SDH, but glomeruli were all negative in control patients (77). In cultured rat mesangial cells, SDH activity was clearly detected (79). Na/ Myo-inositol cotransporter mRNA was detected predominantly in the papilla and inner medulla endothelial, epithelial, interstitial, and collecting duct cells; in the outer medulla collecting duct, endothelial, and thin limb cells; and in the cortex, Bowmans capsule, glomerular tuft, collecting duct, and distal convoluted tubule cells (76). 3. In vitro evidence for AR effects on renal cells. During hyperglycemia, glucose levels rapidly increase in tissues, such as the kidney, that are insulin-independent for glucose uptake. Excess glucose enters the polyol pathway and activates AR, but because SDH activity does not increase similarly, sorbitol accumulates (69). To explain the role of the polyol pathway in the onset of diabetic complications, different mechanisms have been proposed: accumulation of sorbitol or fructose (68, 69), myo-inositol depletion (70), or alterations in the NADPH/NADP and NADH/NAD ratios (80). In cultured rat mesangial cells, enhanced expression of the facilitative glucose transporter 1 increased AR expression and activity, polyol accumulation, and PKC levels, which may induce stimulation of matrix protein synthesis (81). In addition, in cultured mesangial cells, high glucose-induced DAG accumulation, PKC activation, and TGF- overproduction were mediated through polyol pathway activation (82, 83). In cultured proximal tubular cells, PKC and polyol pathway activation mediated the high glucose-induced collagen and fibronectin accumulation by decreasing their degradation (84 86). In proximal tubular cells, glucose increased sorbitol, fructose, DAG levels, PKC activity, and the expression of angiotensinogen (87), but not AR mRNA, immunoreactivity, and activity, which may be explained by a negative feedback of intracellular sorbitol accumulation on AR gene transcription (84, 88). 4. Experimental evidence for a role of AR in diabetic kidney disease. Both short- and long-term experimental type 1 diabetes are associated with increased renal sorbitol and fructose levels (65, 89 93). Renal myo-inositol levels were found to be increased (92, 94) or decreased in diabetic animals (95). More specifically, renal polyol accumulation was associated with a decrease in myo-inositol levels in the kidney cortex while being unchanged in the kidney medulla (93). Renal AR level and activity were elevated in diabetic rats, but renal SDH level or activity did not change (92, 96). However, one study found a decrease in glomerular AR expression in type 1 diabetic rats after 2 wk of diabetes, whereas the expression of AR did not change in glomeruli and renal arterioles of type 2 diabetic rats (97). NaK-ATPase activity was reduced in glomeruli of diabetic animal models (95). In contrast, renal NaK-ATPase activity was unaffected in another study (93). Despite the discrepancy of these results, which may be due to variations in quantification methods, duration of diabetes, degree of hyperglycemia or animal strain, the ma-

1. The AR system. AR is a member of the aldo-keto reductases (AKR), a superfamily of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductases with potential roles in the detoxification of aldehydes and ketones (68). The family of AR consists of 11 members, named AKR1B1 to AKR1B11 (AKR homepage, http://www.med.upenn.edu/ akr). AR catalyzes the reduction of glucose to sorbitol, the first and the rate-limiting step in the polyol pathway (68). Sorbitol metabolism is also governed by sorbitol dehydrogenase (SDH), the enzyme responsible for the degradation of sorbitol to fructose using NAD (69). Sorbitol may interfere with the uptake and metabolism of myo-inositol (70). The physiological role of the AR pathway remains largely unknown. However, AR, sorbitol and myo-inositol are thought to play a role in the osmoregulation of the kidney (71). In most mammalian cells, the intracellular concentration of myo-inositol is many times higher than in the circulation by virtue of a Na/myo-inositol cotransporter (72). Species- and organ-specific ARs have been implicated in hormone-regulated apoptosis (73) and hormone production (74). 2. Expression of AR in the normal kidney. A single form of AR is expressed in human kidney (75). AR mRNA, protein, and enzyme activity were mainly found in the inner medulla (76). AR mRNA expression was pronounced in the papilla, especially in collecting duct cells, epithelial, endothelial, interstitial, and thin limb cells, and weak in the outer medulla and cortex, particularly in cells of the collecting duct, Bowmans capsule, and the glomerular tuft (76, 77). AR protein was localized to podocytes and distal convoluted tubules (78). AR activity was detected in mesangial cells in culture (79), but not in vivo (77, 78). SDH mRNA expression was highest in the cortex, in Bowmans capsule, glomerular tuft, collecting duct, peritubular endothelial and interstitial cells, and moderate in

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jority of the published studies point toward activation of the polyol pathway and sorbitol accumulation in diabetes. In contrast to diabetic dogs showing nephromegaly, glomerular hypertrophy, mesangial expansion, BMT, and albuminuria, dogs fed galactose for 5 yr only developed thickening of the glomerular basement membrane (91). Kidney polyol accumulation was much more pronounced in galactose-fed dogs than in diabetic dogs, suggesting that the accumulation of polyol per se is not sufficient to produce diabetic glomerulopathy (91). Transgenic mice overexpressing human AR developed pathological changes in the kidney, i.e., thrombi of renal vessels and fibrinous deposits in Bowmans capsules (98). 5. Clinical evidence for a role of AR in diabetic kidney disease. Data about the polyol pathway and diabetic nephropathy in type 1 diabetic patients are rather scarce. In peripheral blood mononuclear cells obtained from type 1 diabetic patients with diabetic kidney disease, AR expression was increased compared with that in normal subjects, type 1 diabetics without nephropathy, and nondiabetic subjects with renal disease (99). Studies on AR gene polymorphisms have implicated the polyol pathway in the development of kidney complications, because the presence of the Z-2 allele or the T allele of the AR gene in type 1 diabetic subjects was associated with an increased risk for diabetic nephropathy (100, 101). Type 2 diabetic patients had higher serum and urine myo-inositol concentrations and sorbitol excretion than healthy controls (102, 103), but urinary fructose excretion was not different between the groups (103). Improvement of glycemic control reduced the urinary myo-inositol excretion (103). Serum myo-inositol concentrations were higher in patients with nephropathy than in those without nephropathy, but there were no differences in urinary myo-inositol concentrations (102). Renal AR expression was increased in type 2 diabetic patients compared with controls (77), especially in the glomerular mesangial area of patients with nephropathy (77). Reduced tubular SDH expression in diabetic patients was associated with interstitial fibrosis and thickened basement membranes (77). 6. Agents with effects on the AR system in diabetic kidney disease. Numerous experimental and clinical studies with different ARIs have implicated the diabetes-induced polyol pathway activation in the development of diabetic retinopathy and neuropathy, but only a few studies have investigated the influence of ARIs in the diabetic kidney. Despite the large number of compounds active against AR in vitro, only two classes of ARIs can be reported regarding in vivo activity: cyclic imides (mostly spirohydantoins) and carboxylic acid derivatives with sorbinil and tolrestat being the most representative members, respectively (104). However, due to toxicity or a lack of efficacy, sorbinil, tolrestat, and ponalrestat have been withdrawn from clinical trials. In the following will be focused mainly on epalrestat, the only ARI still available (104). a. ARIs. Tolrestat blocked the glucose-induced increases in sorbitol, fructose, and DAG levels, PKC activity, and angiotensinogen expression in proximal tubular cells (87). Epalrestat abolished the glucose-induced increases in TGF- and

PKC activity in cultured human mesangial cells, providing evidence for an interaction between these glucose-induced pathways (82). In type 1 diabetic rats, short-term oral administration of epalrestat prevented the increase in UAE and the reduction of anionic sites on the lamina rara externa of the glomerular basement membrane (105). In type 1 diabetic rats receiving epalrestat for 2 wk, renal cortical sorbitol concentration and the urinary enzyme excretion were not increased compared with untreated diabetic rats, suggesting that sorbitol accumulation leads to proximal tubular cell dysfunction and abnormal enzymuria (106). Long-term treatment with epalrestat ameliorated the decline of GFR and renal plasma flow (RPF) and mesangial expansion observed in placebo-treated diabetic rats, implicating the polyol pathway in functional and morphological changes in type 1 diabetes (107). In type 1 diabetes, 6 months of AR inhibition with ponalrestat or tolrestat reduced GFR in normo- and microalbuminuric patients, respectively (108, 109). However, 3 months of ponalrestat treatment had no effect on renal hemodynamics in patients with incipient nephropathy (110). In microalbuminuric type 2 diabetic patients, 5 yr treatment with epalrestat prevented the progression of incipient diabetic nephropathy (Fig. 2) (111). The development of new ARIs (112) may provide more potent and specific agents to block the polyol pathway, and future studies are warranted to elucidate their potential in the prevention of the development or progression of diabetic kidney disease. 7. Conclusion. In vitro data clearly demonstrate a link between the polyol pathway, AGEs, PKC, RAS, and TGF- activation in hyperglycemic conditions, which may stimulate the production of ECM proteins. Experimental studies implicate activation of the polyol pathway with sorbitol and fructose accumulation in short- and long-term diabetes, although results on myo-inositol levels and AR activity are not always consistent. Clinical data point toward increased AR activity and myo-inositol levels. Many ARIs have been withdrawn from clinical use due to disappointing results in the treatment of diabetic retinopathy and neuropathy. However, both experimental and clinical studies indicate beneficial effects of certain ARIs on diabetic structural and functional renal changes.

FIG. 2. Changes in UAE of microalbuminuric patients treated with (F) and without (E) epalrestat. Vertical bars indicate means SEM. *, P 0.01 vs. 0 yr. #, P 0.05 vs. patients without epalrestat. [Reproduced with permission from K. Iso et al.: J Diabetes Complications 15:241244, 2001 (111). Elsevier.]

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III. Hemodynamic Factors A. Angiotensin II (Ang II)/renin-angiotensin system (RAS)

1. The Ang II system. Apart from the circulating RAS that regulates blood pressure, fluid, and electrolyte balance, many tissues, including the kidney, appear to have an independently regulated local RAS (113). Renin, produced in the juxtaglomerular cells of the kidney, converts angiotensinogen, derived primarily from hepatocytes, to inactive Ang I, which is then converted to biologically active Ang II by ACE (113). Ang II exerts hemodynamic and nonhemodynamic effects by binding to the Ang II type 1 (AT1) or Ang II type 2 (AT2) receptors. Most of the intrarenal actions of Ang II are mediated by AT1 receptors that signal through activation of phospholipases and PKC and inactivation of adenylate cyclase (113). The role of AT2 receptors in kidney has not yet been clearly defined, but involves the production of NO and prostaglandin F2 and signal transduction through activation of guanylate cyclase, phosphatases, and potassium channels (113). AT2 receptors might also be involved in mediating proliferation and apoptosis (114), and they counteract the effects of AT1 receptor-mediated Ang II actions. 2. Expression of Ang II/RAS in the normal kidney. All components of the RAS, i.e., renin, angiotensinogen, ACE, Ang II, AT1 and AT2 receptors are expressed in normal kidney (113). Renin mRNA was identified in cultured human mesangial cells and glomerular podocytes (115). In rat and human kidney, renin mRNA or protein expression was detected in glomerular endothelial cells and proximal and distal tubular cells (115, 116). Angiotensinogen mRNA was observed in cultured human glomerular podocytes and mesangial cells (115) and rat proximal tubule suspensions (116). In human kidney, a tubular angiotensinogen mRNA distribution was found (115). ACE mRNA was detected in cultured human mesangial cells and glomerular podocytes, in rat proximal tubules (116), and in tubules in human kidney (115). Most of the intrarenal Ang II is formed within the kidney (113). In rat kidney, AT1 receptors were detected in afferent arterioles, arcuate arteries, vasa recta, glomerular mesangial cells and podocytes, proximal tubules, thick ascending limb, collecting ducts, and medullary interstitial cells (117). AT2 receptors were localized in afferent arterioles, arcuate arteries, vasa recta, glomerular cells, proximal tubules, collecting ducts, and interstitial cells (117119). 3. In vitro evidence for Ang II on renal cells. High glucose stimulated the mRNA expression and protein synthesis of angiotensinogen in proximal tubular epithelial cells and involved activation of the polyol pathway and PKC (87). In cultured rat mesangial cells, high glucose increased Ang II production and AT2 receptor expression and reduced the levels of aminopeptidase A, a metalloprotease that degrades Ang II, which could contribute to the increase of Ang II (120, 121). In cultured mesangial cells, the high glucose-induced inhibition of collagenase activity, reduction of MMP-2 levels, and increase in TGF-1 secretion, resulting in decreased matrix degradation and increased matrix accumulation, are mediated by Ang II (121). Ang II-induced ET-1 production in glomerular mesangial cells is partially PKC-dependent (122)

and plays a role in the mitogenic effect of Ang II (123). Ang II induced connective tissue growth factor (CTGF) in cultured mesangial and tubular epithelial cells (124). Ang II induced apoptosis in cultured proximal tubular cells (125). 4. Experimental evidence for a role of Ang II in diabetic kidney disease. Although the role of RAS in diabetic nephropathy is indisputable, data concerning the influence of diabetes on systemic and intrarenal RAS have been conflicting (126). In experimental type 1 and type 2 diabetes, plasma levels of RAS components have generally shown suppression of the system, and the local glomerular RAS seems to be activated, but data are variable, which may be due to the degree of hyperglycemia or the time after onset of diabetes (126). STZdiabetic rats tended to have increased plasma and intrarenal levels of Ang II compared with control and insulin-treated rats (116). Studies investigating renin, angiotensinogen, and ACE mRNA in the proximal tubules (116) and glomeruli (119) in rats with STZ diabetes for 2 wk only showed an increase in renin mRNA in the proximal tubules. A downregulation of cortical and proximal tubular AT1 receptors (116) and of AT2 receptors in all kidney regions (119) was reported, suggesting that alterations in the balance of kidney AT1 and AT2 receptors may contribute to Ang II-mediated diabetic glomerular injury. In diabetic (mRen-2)27 transgenic rats, diabetic renal pathology was associated with intense renin mRNA and protein in proximal tubules and juxtaglomerular cells along with overexpression of TGF-1 and collagen IV mRNA in glomeruli and tubules, as well as a declining GFR and UAE (127). 5. Clinical evidence for a role of Ang in diabetic kidney disease. In type 1 diabetic patients, hyperglycemia was associated with increased plasma renin concentrations, whereas in patients with type 2 diabetes and nephropathy plasma renin levels were suppressed (126). However, measurements of circulating components of the RAS do not appear to accurately predict the state of activation of the local RAS (126). One study found stronger signals for renin, angiotensinogen, and ACE mRNA in mesangial and epithelial cells from hypertensive patients and patients with renal pathology, including some with diabetes (115). In renal biopsy specimens from type 2 diabetic patients, enhanced glomerular ACE staining was reported, especially in diabetics with glomerular nodular lesions (128). Another study reported reduced AT1 receptor mRNA levels in kidney biopsy samples from type 2 diabetics with nephropathy when compared with controls (129). Several studies investigating polymorphisms of the ACE and angiotensinogen genes that may predispose people with diabetes to nephropathy have yielded varying outcomes. The TT genotype of the angiotensinogen M235T polymorphism has been associated with diabetic nephropathy in type 1 diabetes (130), whereas other studies in type 1 and type 2 diabetic subjects failed to find an association (131133). The D-allele of the ACE insertion/deletion (I/D) polymorphism has been identified as a risk factor for increased progression of diabetic glomerulopathy in microalbuminuric type 1 diabetic patients (134). However, other studies in type 1 (132) and type 2 diabetic patients (133) did not support a role for ACE I/D polymorphism in the development of di-

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abetic nephropathy. A metaanalysis of the ACE I/D polymorphism and risk of diabetic nephropathy, including 11 studies in type 1 and 10 studies in type 2 diabetic patients, suggested that the ACE I/D polymorphism contributes to the genetic susceptibility to diabetic nephropathy in Japanese but not in Caucasian type 2 diabetic patients (135). In Caucasian type 1 diabetic patients, comparison of data was complicated by differences between study populations, but a trend toward a protective effect of the II genotype on the development of increased UAE was observed (135). The risk for diabetic nephropathy in type 1 diabetic patients was similar in carriers and noncarriers of the AT1 receptor A1166C polymorphism (132). 6. Agents with effects on the Ang II system in diabetic kidney disease. The best known agents to target the RAS are ACEi and the newer ARBs. ACEi act in part by reducing plasma Ang II levels and increasing plasma bradykinin levels (136). Bradykinin accumulation has been associated with side effects, including cough and angioedema, but may also contribute to the antihypertensive and vasculoprotective effects of ACEi. ACEi do not provide a complete inhibition of Ang II activity, because Ang II can be formed through non-ACE pathways. ARBs might exert a more specific and complete blockade of the RAS through their inhibition of the actions of Ang II at the AT1 receptor, but this results in higher circulating Ang II levels (137). The biological activity of Ang II or its metabolites may be more directed to other Ang II binding sites with potential adverse effects (138). In addition, ARBs raise bradykinin levels through stimulation of AT2 receptors by elevated Ang II levels. Thus, ACEi and ARBs potentially have additive effects on both the RAS and bradykinin levels (136). The potential role of oral renin inhibitors that decrease Ang II levels in humans and of AS-ODNs designed to target renin, angiotensinogen, ACE, or AT1 receptors in the therapy of diabetic nephropathy remains to be investigated. a. ACEi. ACEi consistently limited progressive renal injury in experimental models of STZ-induced diabetes (139). In Wistar fatty rats, an experimental model of type 2 diabetes with progressive kidney disease, enalapril ameliorated both existing proteinuria and the progression of proteinuria and preserved glomerular structure (5). In microalbuminuric type 1 diabetic subjects, perindopril reduced glomerular BMT and tended to reduce interstitial fibrosis (140), and enalapril prevented glomerular growth (141) and progression of glomerulopathy, indicating that ACE inhibition may influence renal structural changes (142). However, in a small cohort of normotensive type 1 diabetic patients with albuminuria and diabetic glomerulopathy, enalapril treatment did not affect renal structure (143). In normotensive normoalbuminuric type 1 diabetic patients, acute ACE inhibition by enalapril caused a decline in filtration fraction and in blood pressure but had no effect on UAE (144); 6 wk of captopril treatment had no effect on GFR and UAE (145), but treatment with enalapril for 3 months reduced UAE without effect on GFR or RPF (144). In normotensive microalbuminuric type 1 diabetic patients, UAE and blood pressure were reduced, whereas GFR was unaffected by long-term treatment with ramipril (146) or perindopril (147). In micro- and

macroalbuminuric type 1 diabetic patients, acute ACE inhibition by enalapril did not change GFR, but it reduced blood pressure, UAE, filtration fraction, and renal vascular resistance, whereas RPF tended to rise (148). Six months of enalapril treatment induced similar changes except for GFR and RPF; GFR was reduced, whereas RPF remained unchanged (149). Enalapril was more effective in reducing UAE in proteinuric type 1 diabetic patients than antihypertensive patients (148). In normotensive type 1 diabetics with nephropathy treated for 8 yr with captopril, systemic blood pressure and albuminuria remained unchanged and only a minimal loss of GFR was seen when compared with patients who were not treated with captopril (150). However, captopril treatment was associated with a 50% risk reduction of the combined end points of death, dialysis, and transplantation (Fig. 3) (151). In macroalbuminuric type 1 diabetic patients with mild to moderate hypertension, treatment with enalapril reduced UAE, total protein excretion, and blood pressure, but had no effect on GFR and RPF (152). In microalbuminuric type 2 diabetic subjects, perindopril also reduced glomerular BMT and tended to reduce interstitial fibrosis (140). In micro- and macroalbuminuric type 2 diabetic patients with urinary podocyte excretion, trandolapril treatment reduced the number of podocytes excreted in the urine (153). The abnormalities in size-selective function of the glomerular barrier in type 2 diabetics with overt nephropathy were not ameliorated by ACEi or calcium channel blockade at variance to type 1 diabetes (154). Enalapril attenuated the decline in renal function and reduced the extent of albuminuria in normotensive, normo- and microalbuminuric patients with type 2 diabetes (155, 156). In hypertensive type 2 diabetic patients with normo-, micro-, or macroalbuminuria, treatment with enalapril was associated with a greater reduction in UAE than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril (157). b. ARBs. In diabetic Wistar fatty rats, candesartan treatment for 4 wk prevented an increase in proteinuria and development of glomerular lesions (5). In Zucker diabetic fatty (ZDF) rats, a model of obese type 2 diabetes, 19 wk of treatment with olmesartan suppressed proteinuria, corrected hyperlipidemia and hypoalbuminemia, and reduced tubular and glomerular damage in ZDF rats, indicating that the renoprotective effect of olmesartan is, at least in part, independent of its antihypertensive effect (158). Recent clinical trials with irbesartan in type 2 diabetic patients with microalbuminuria (IRMA2) (Fig. 4) (159) or nephropathy (IDNT) (160) and with losartan in patients with type 2 diabetes and nephropathy (RENAAL) (161) have demonstrated the renoprotective effects of ARBs independently of their blood pressure-lowering effect. A clinical trial with valsartan in high-risk patients with type 2 diabetes is ongoing (ABCD-2C) and will compare the effect of intensive vs. moderate control of blood pressure on diabetic complications and mortality. c. Combination of ACEi and ARBs. In renin transgenic rats, the combination of enalapril and losartan resulted in higher

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athy and hypertension despite ACEi treatment, the addition of irbesartan or candesartan, respectively, reduced blood pressure and albuminuria more effectively than ACEi alone (165, 166). In the Candesartan and Lisinopril Microalbuminuria Study (CALM) in microalbuminuric type 2 diabetic patients with hypertension, combination therapy afforded greater reductions in blood pressure and albuminuria than either drug alone (167). 7. Conclusion. Data regarding the renal expression of RAS components are inconsistent. Furthermore, the contribution of ACE or angiotensinogen polymorphisms to the development or progression of diabetic nephropathy remains controversial. Nevertheless, the beneficial effects of ACEi and/or ARBs on diabetic renal structural and functional changes beyond their blood pressure-lowering effect provides substantial experimental and clinical evidence for a deleterious role of RAS components in diabetic nephropathy. The combination of ACEi and ARBs seems to have an additive effect, at least on blood pressure and UAE. The effects of ACEi on renal structure and function may be partly explained by effects on growth factors and cytokines, metabolic pathways, and signaling molecules.
B. Endothelin (ET)

FIG. 3. Cumulative incidence of events in patients with diabetic nephropathy in the captopril and placebo groups. A, The cumulative percentage of patients with the primary end point: a doubling of the baseline serum creatinine concentration to at least 2.0 mg/dl. B, The cumulative percentage of patients who died or required dialysis or renal transplantation. The numbers at the bottom of each panel are the numbers of patients in each group at risk for the event at baseline and after each 6-month period. [Reproduced with permission from E. J. Lewis et al.: N Engl J Med 329:1456 1462, 1993 (151). Massachusetts Medical Society.]

1. The ET system. The ET system comprises the ETs, two receptors, and two activating peptidases. The ETs are a family of structurally and functionally related peptides, more in particular ET-1, the most potent vasoconstrictor known, ET-2, and ET-3. Preproendothelins, the ET precursors, are cleaved by endopeptidases to form inactive intermediates termed big ETs. Big ETs are then cleaved by ET-converting enzymes (ECEs) to form the final products (168, 169). In mammals, the two ET receptors, ETA and ETB, signal through the activation of G-proteins, phospholipase C, and PKC. ETA receptors are involved in vasoconstriction and cell proliferation, whereas ETB receptors binding all ETs mediate NO release and transient vasodilation (168, 169). ETs are normally not circulating hormones but act as paracrine and autocrine factors. The (patho)physiological roles of ETs in various organs have been described in detail (170). In the kidney, the ET system regulates renal hemodynamics, water and sodium homeostasis, cell proliferation, and matrix formation (168 170). 2. Expression of ET in the normal kidney. ET-1, ET-2, and ET-3, ECE-1, and receptors ETA and ETB are present in the kidney (169, 171). ET-1 is found in all parts of the nephron. ET-1 is synthesized and secreted by cultured glomerular mesangial (122, 172174), epithelial (175), and endothelial cells (176) and proximal tubular cells (177). In porcine kidney, the concentration of immunoreactive ET-1 was highest in renal inner medulla and very low in cortex (178). In rat kidney, ET-1 mRNA was demonstrated in cortical and medullary collecting ducts (179). In human kidney, mature ET and big ET-1 localized to the endothelium of glomeruli and intrarenal blood vessels (176). All three ET isoforms were detected by RT-PCR in human homogenates of renal medulla, cortex, and vessels (176). ET-3 is distributed differently along the nephron than ET-1 in rat kidney (180). ECE-1 localized to

plasma renin levels than either drug alone, suggesting an additive inhibition of the RAS by combination therapy (162). In an experimental model of diabetic nephropathy, combination therapy with valsartan and perindopril lowered blood pressure and improved severe diabetic glomerulosclerosis better than monotherapy but was equally effective at ameliorating renal function and reducing albuminuria (163). The combination of irbesartan and captopril in diabetic spontaneously hypertensive rats demonstrated additive hypotensive and antialbuminuric effects compared with monotherapy (164). These data, however, do not allow clear distinction between the additive effects of combination therapy on blood pressure vs. additive intrinsic renoprotective effects. In type 1 and type 2 diabetic patients with nephrop-

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FIG. 4. Incidence of progression to diabetic nephropathy during treatment with 150 mg of irbesartan daily, 300 mg of irbesartan daily, or placebo in hypertensive patients with type 2 diabetes and persistent microalbuminuria. The difference between the placebo group and the 150-mg group was not significant (P 0.08 by the log-rank test), but the difference between the placebo group and the 300-mg group was significant (P 0.001 by the log-rank test). [Reproduced with permission from H.-H. Parving et al.: N Engl J Med 345:870 878, 2001 (159). Massachusetts Medical Society.]

vascular endothelial and tubular epithelial cells in the cortex and medulla of human kidney (171). Both ETA and ETB receptor mRNAs were expressed in human mesangial cells (181), in rat glomeruli (182), and in normal human renal cortex and medulla with ETB predominating (183). 3. In vitro evidence for ET effects on renal cells. Various agents increase ET-1 production by mesangial cells, including hyperglycemia, PDGF, TGF-1, thrombin, Ang II, and ET-1 (181). ET-1 release is also increased by thrombin and bradykinin in glomerular endothelial cells (184) and by TGF- in collecting duct cells (185). Other factors such as shear-stress due to glomerular hyperfiltration (186) and urine flow (187) have been shown to stimulate ET-1 synthesis or release. Furthermore, AGEs induced ET-1 mRNA expression in cultured proximal tubular cells (188). High glucose modified the responses of mesangial cells to ET-1 (181). For example, hyperglycemia augmented ET-1-stimulated 1 (IV) collagen production and MAPK activity in mesangial cells, effects that are PKC dependent and associated with altered translocation of PKC and PKC (181, 189). ET-1 stimulates mesangial cell proliferation, contraction, and ECM accumulation (176). 4. Experimental evidence for a role of ET in diabetic kidney disease. Studies examining systemic and intrarenal ET-1 levels in diabetic animals have yielded conflicting results. In STZdiabetic rats, plasma ET-1 levels have been undetectable (190), unchanged (191), enhanced (187, 192), or suppressed (193) compared with control rats. Urinary ET-1 excretion was increased in STZ-diabetic rats, in parallel with enhanced proteinuria (139). Renal ET-1 levels were reported to be unchanged (190) or reduced (191) and glomerular ET-1 levels were enhanced (182) in STZ-diabetic vs. control rats. In early STZ-diabetic rats, no difference in glomerular ETA receptor characteristics has been found; however, a reduction in ETB density, as well as a reduction in glomerular Ang II receptor density has been reported (194). The mRNA levels for ETA and ETB did not change in STZ-diabetic rats (182). In type 2 diabetic rats, glomerular and tubulointerstitial ET-1 mRNA and protein expression was higher than in nondiabetic rats (195). The intrarenal ET system could be affected indepen-

dently of the systemic ET-1 system. Discrepancies may be related to the degree of hyperglycemia, the renal localization, or varying duration of diabetes. Up-regulation of the renal ET system might favor the development of renal lesions, as suggested by in vivo studies in transgenic mice and rats. ET-1 transgenic mice with only slightly elevated tissue and plasma ET-1 concentrations developed glomerulosclerosis, interstitial fibrosis, renal cysts, and a progressive decline in GFR (196). ET-2 transgenic rats with a high renal transgene expression almost exclusively within glomeruli developed glomerulosclerosis and albuminuria without a change in GFR (197). 5. Clinical evidence for a role of ET in diabetic kidney disease. Few clinical studies have been published on ET in diabetic kidney disease. In patients with uncomplicated type 1 diabetes, the plasma concentrations of ET-1 were increased and directly correlated to those of von Willebrand factor, and inversely correlated to plasma concentrations of fibronectin (198). Plasma ET-1 levels were higher in nonsmoking normotensive type 2 diabetic patients than in controls and higher in microalbuminuric vs. normoalbuminuric patients (199). Plasma ET-1 concentrations were increased in hypertensive type 2 diabetic patients as compared with healthy control subjects but were not different from those in normotensive patients (200). In contrast, plasma ET-1 levels were equally elevated in type 1 and type 2 diabetic patients and hypertensive nondiabetic patients compared with healthy controls, but the diabetic groups included patients with and without hypertension (201). Plasma ET-1 levels did not correlate with clinical parameters of diabetic disease progression in diabetic patients, but correlated with age and systolic blood pressure in healthy controls (201). In addition, plasma and urinary ET-1-like immunoreactivity values correlated positively with the severity of diabetic nephropathy in type 2 diabetics (202). In contrast, another study found no differences in the diurnal urinary excretion of immunoreactive ET among diabetic patients and patients with nondiabetic diseases (203). 6. Agents with effects on ET in diabetic kidney disease. Several agents are available to inhibit the action of ET, including

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neutralizing antibodies against ET and ET receptors and AS-ODNs to preproendothelin-1, ECE, and the ETA receptor. However, the potential use of these substances in the treatment of diabetic renal changes has not been explored, except for some in vitro studies. Ample experimental studies focused on the renoprotective effects of ET receptor antagonists. The ET system can be targeted indirectly by ACEi and PKC inhibitors. a. Neutralizing antibodies. Addition of a neutralizing anti-ET antibody to mesangial cell cultures markedly augmented the secretion and activation of MMP-2, whereas addition of exogenous ET-1 inhibited the synthesis of MMP-2. These results implicate ET as a potential factor in pathophysiological matrix turnover in the glomerulus (204). b. AS-ODNs. AS-ODNs targeting preproendothelin-1 mRNA were delivered into cultured human mesangial cells and inhibited ET-1 secretion and the cell proliferation. These results identify ET-1 as one of the autocrine growth factors of human mesangial cells that may be important in pathophysiological conditions characterized by mesangial proliferation (205).

c. ET receptor antagonists. The effects of ETs can be blocked by the administration of nonselective ET receptor antagonists (bosentan, PD 142893, TAK-044, LU 224332), selective ETA antagonists (FR139317, BQ-123, BMS-193884, LU 135252, PD156707, and EMD 94246), or ETB antagonists (RES-701-1, BQ-788). PD 142893 reduced UAE in diabetic animals (206). In nondiabetic and STZ-diabetic (mRen-2)27 rats, oral administration of bosentan for 12 wk normalized systolic blood pressure and attenuated the diabetes-associated decline in GFR (127). Despite producing normotension, severe diabetic renal pathology was not prevented by bosentan, suggesting dissociation of ET, UAE, and hypertension from the structural injury in this diabetic model (Fig. 5) (127). Selective ETA blockade with FR139317 has shown protective effects in experimental diabetic glomerulopathy (192). In STZ-diabetic rats, mRNA levels for various collagens, laminin, and growth factors were elevated (192) and glomerular proliferating cell nuclear antigen, c-myc, c-fos, and c-jun mRNA levels increased with progression of diabetic nephropathy (207). These changes were reduced by FR139317 (207), suggesting that ET may play a role in ECM production. Thus, ET inhibition may protect against diabetic glomerular injury, pos-

FIG. 5. Histopathology of the kidney cortex in nondiabetic and diabetic transgenic (mREN-2)27 rats treated for 12 wk with either valsartan or bosentan. Sections are stained with periodic acid-Schiff. G, Glomerulus. A, In nondiabetic rats, there is minimal evidence of glomerulosclerosis. B, Diabetic rats have severe glomerulosclerosis, arteriolar hyalinization (asterisk). Valsartantreated nondiabetic (C) and diabetic rats (D) and bosentan-treated nondiabetic rats (E) have minimal evidence of glomerulosclerosis. Bosentan-treated diabetic rats (F) have severe glomerulosclerosis and cortical interstitial fibrosis (arrow; magnification, 300). [Reproduced with permission from D. J. Kelly et al.: Kidney Int 57:18821894, 2000 (127). Blackwell Publishing.]

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sibly by interference with growth factors and growth-related genes (192). LU 135252 prevented the Ang II-induced increase in tissue ET-1 content and functional ECE activity in rats (208). Furthermore, LU 135252 prevented renal histological alterations in STZ-diabetic rats, and decreased urinary ET-1 excretion, but had no effect on UAE (209). Both LU 135252 and LU 224332 reduced proteinuria and completely normalized the renal matrix expression of type IV collagen and fibronectin in hyperglycemic rats with STZ-induced diabetes (210). d. ACEi. Lisinopril attenuated the increased renal ET-1 expression in STZ-diabetic rats and had better blood pressure-lowering but similar renoprotective effects than the unselective ETA/ETB receptor antagonist, PD 142,893 (206). Treatment with enalapril or nicardipine similarly reduced the elevated plasma ET-1 levels in hypertensive type 2 diabetic patients to control levels. The change in plasma ET-1 level was not correlated to the change in blood pressure or to UAE (200). e. PKC inhibition. The ET-1-induced MAPK activation in mesangial cells is PKC dependent and associated with altered translocation of PKC and PKC (189). Infusion of the specific PKC inhibitor 1-(6-isoquinolinesulfonyl) piperazine reversed the down-regulation of ET receptors in association with normalization of PKC activity in STZ-diabetic rats (194). 7. Conclusion. Various renal cell types can secrete ET-1 in vitro, which can be stimulated by glucose, Ang II, TGF-, and PDGF. Experimental data regarding plasma and renal ET-1 levels are conflicting, but experiments in transgenic animals clearly show that up-regulation of ET-1 or ET-2 may favor the development of structural and functional renal changes. In type 1 and type 2 diabetic patients, increased plasma ET-1 levels correlate with the severity of diabetic nephropathy. In vitro application of neutralizing ET antibodies and AS-ODNs indicates ET-1 as a potential factor in mesangial proliferation and matrix turnover. A strong argument in favor of ET-1 as a mediator of renal injury derives from studies with ET receptor antagonists in experimental diabetes. Independent of their blood pressure-lowering effect, ET receptor antagonists reduced renal ET-1 content, urinary ET-1 excretion, and the production of ECM proteins; lowered UAE; and reduced renal expression of TGF- and PDGF-B.
C. Nitric oxide (NO)

structural integrity (213). Endogenous inhibitors of NOS are NG-monomethyl-l-arginine (l-NMMA) and asymmetric dimethylarginine (ADMA), substances naturally occurring in human plasma (214). ADMA is mainly cleared by the enzyme dimethylarginine-dimethylaminohydrolase (DDAH) and partly by renal secretion (215). 2. Expression of the NO system in the normal kidney. All three NOS isoforms are present in the kidney (211). Their localization and that of alternative splice variants have been described in detail (216). The renal medulla is the main site for NO synthesis in the kidney (216). NOS1 mRNA and protein were detected abundantly in the macula densa and in some thick ascending limb cells in rat and human kidney (217, 218). In addition, NOS1 immunoreactivity has been demonstrated in the endothelium of glomerular efferent arterioles, inner medullary collecting ducts, and the parietal epithelium of Bowmans capsule in rat kidney (217, 218). In rat and human kidney, NOS3 was typically detected in the endothelium of preglomerular, glomerular, and postglomerular vessels, whereas NOS2 was hardly detected (217, 219). In human glomeruli NOS3 mRNA was constitutively expressed, whereas NOS2 mRNA expression was barely found, and NOS1 mRNA was not detectable (220). 3. In vitro evidence for NO effects on renal cells. Most studies in cultured renal cells have provided evidence that diabetes is a state of NO deficiency (211). For example, high glucose attenuated the detectable NO, blunted the NO responses to NOS3 agonists in human endothelial cells (221), and inhibited NO synthesis in murine mesangial cells (222). Possible mechanisms whereby high glucose decreases NO bioavailibility include NO capture by glucose (221), superoxide anion generation (223), endothelial ADMA accumulation (215), l-arginine depletion, and reduced tetrahydrobiopterin stability and availability (222). Other studies, however, in cultured mesangial cells, documented the stimulation of NO production in hyperglycemic conditions (224, 225), which may involve NOS2, PKC, and AR activation (224). NO deficiency as well as increased NO production may promote ECM accumulation in the mesangium (224, 226). The in vitro assessment of renal vascular reactivity in isolated rat kidneys and isolated renal arteries has provided more controversial evidence, suggesting increased, normal, or decreased NO synthesis and activity. Some of the discrepancies between different studies could relate to the method of preconstriction of isolated vessels (211). 4. Experimental evidence for a role of NO in diabetic kidney disease. Research on the effect of experimental diabetes on the renal expression of NOS isoforms has also yielded conflicting results (reviewed extensively in Ref. 211). At 7 d of STZdiabetes, total cortical NOS activity was reduced and associated with decreased NOS1 mRNA and NADPH diaphorase staining in the macula densa, whereas cortical NOS3 was not different between diabetic and control rats (227). In contrast, after 2 wk of STZ-diabetes, NOS3 protein levels and immunostaining were elevated in glomerular endothelial cells and preglomerular vessels in diabetic vs. control rats (228, 229). However, another study found no differences in renal cortical expression of NOS isoforms or in diaphorase staining

1. The NO system. NO is a widespread signaling molecule that plays a major role in nearly every cellular and organ function in the body. The enzymatic formation of NO from l-arginine, generating l-citrulline as a coproduct, is catalyzed by NOS. Three mammalian NOS isoforms have been identified, neuronal (nNOS), endothelial (eNOS), and macrophage or inducible NOS (iNOS), more recently termed NOS1, NOS2, and NOS3, respectively (211). Their structure, function, and inhibition has been reviewed extensively (212). NO mediates its effects through activation of guanylate cyclase, resulting in increased levels of cyclic GMP (cGMP). In the kidney, NO is involved in the regulation of RPF, GFR, sodium excretion, extracellular fluid volume, and the maintenance of renal

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between control and diabetic rats (230). After 4 wk of STZdiabetes, NOS1 immunostaining was modestly enhanced in macula densa (218), whole kidney NOS2 and NOS3 mRNA levels were unchanged (231), but NOS3 protein expression was increased, and NOS1 protein expression was unaltered in whole kidney samples (232). After 6 wk of STZ-diabetes, medullary NOS1 and NOS3 mRNA levels were elevated, immunostaining for NOS1 and NOS3 was increased in the proximal straight tubules and medullary thick ascending limb (233), and enhanced NOS3 immunostaining was also found in purified renal vascular trees (Fig. 6) (234). Data concerning the role of NO in glomerular hyperfiltration in experimental diabetes are also conflicting (reviewed extensively in Ref. 211). The majority of studies in type 1 diabetic rats found glomerular hyperfiltration in the presence of increased urinary NO2 and NO3 (NOx) excretion, supporting the notion that increased NO synthesis contributes to diabetic hyperfiltration (228, 233238). The NO-donor glyceryl trinitrate induced renal vasodilation in control but not in diabetic rats, providing further evidence for a role of enhanced NO production and/or signaling that is not changed by additional NO (236). However, other studies suggested a defect in renal NO production and/or action in experimental diabetes. In rats with type 1 diabetes for 1 to 2 wk, increased CrCl and renal hypertrophy were accompanied by a decreased NOx excretion and unchanged plasma NO metabolites when compared with nondiabetic controls (227, 230). Reduced NO-dependent renal vasodilation (239, 240) and decreased glomerular NO-dependent cGMP generation (239, 241) were reported in diabetic rats compared with controls. The impaired glomerular NO-dependent cGMP generation may be mediated by thromboxane A2 and PKC activation (241) or by an impaired activity of guanylate cyclase (231). NO has been generally considered as the principal mediator of endothelium-dependent vasodilation. En-

dothelium-dependent (i.e., NOS3-dependent) vasodilation is impaired in diabetic animal models and in humans with type 1 and 2 diabetes (242). In the renal circulation of STZ-diabetic rats in vivo, the vasodilation to intrarenal acetylcholine was reduced compared with control rats, suggesting impaired endothelium-dependent vasodilation (243). NO-dependent vasodilation was enhanced, whereas the vasodilation mediated by endothelium-derived hyperpolarizing factor was severely impaired (243). 5. Clinical evidence for a role of NO in diabetic kidney disease. Normoalbuminuric type 1 diabetic subjects had a higher whole-body NO synthesis than control subjects as quantified by measuring the urinary excretion of 15N-nitrate after the iv administration of l-[15N]2-arginine (244). A weak positive relationship was found in the diabetic subjects between the amount of 15N-nitrate excreted and CrCl, supporting an association between NO production and hyperfiltration (244). In microalbuminuric type 1 diabetic patients, serum NOx was independently associated with both UAE and GFR, suggesting a strong link between NO, glomerular hyperfiltration, and microalbuminuria (245). In type 2 diabetic subjects, plasma levels of nitrite, but not nitrate, were higher than in nondiabetic subjects, increased with the progression of diabetic nephropathy, and were positively correlated with AGEs (246). In contrast, one study found serum NOx levels to be lower in type 2 diabetic patients than in controls, and to be higher in males than in females (247). Urinary NOx excretion was higher in normo- and microalbuminuric type 2 diabetic patients with glomerular hyperfiltration compared with controls and macroalbuminuric patients without glomerular hyperfiltration, providing evidence that NO may also contribute to the glomerular hyperfiltration in type 2 diabetes (248). Improvement of metabolic control did not change plasma or urinary NOx levels (249). Plasma ADMA

FIG. 6. Immunocytochemical staining for eNOS in control (left) and diabetic (right) kidneys. Staining is detectable in glomerular capillaries and in afferent and efferent arterioles, visible at the vascular pole of the glomeruli. More capillary profiles are stained in the diabetic glomerulus. [Reproduced with permission from A. S. De Vriese et al.: Kidney Int 60:202210, 2001 (234). Blackwell Publishing.]

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levels correlated with plasma glucose in diabetic and nondiabetic subjects (250). Circulating ADMA levels were higher in untreated type 2 diabetic patients than in matched controls (251, 252), and improvement of glycemic control was associated with decreased plasma ADMA levels (253). Recently, increased ACE activity has been implicated in the mechanism of increased ADMA levels in type 2 diabetic patients (252). However, it is not known whether increased ADMA levels play a role in the development or progression of diabetic nephropathy. 6. Agents with effects on the NO system in diabetic kidney disease. The most frequently used pharmacological inhibitors of NOS are the nonselective l-arginine analogs including Ng-nitrol-arginine methyl ester (l-NAME), l-NMMA, N--nitro-larginine (l-NNA), and aminoguanidine (212). S-Methyl-lthiocitrulline is a partially selective NOS1 inhibitor, and l-imino-ethyl-lysine is a partially selective inhibitor of NOS2 (212). ACEi and ARB, inhibitors of AGE formation and antioxidants, also influence the NO system. a. l-Arginine analogs. Acute systemic infusion of NOS blockers decreased GFR and RPF more in diabetic rats than in control rats (228, 236, 238, 254). Administration of l-NAME to the kidney caused a more pronounced renal vasoconstriction in diabetic rats than in control rats, suggesting that the basal vasodilation in the diabetic renal microcirculation can be attributed to increased NO generation (234). Chronic treatment with l-NAME in STZ-diabetic rats reduced GFR (229, 231, 254, 255) and urinary NOx excretion (229, 231, 255), attenuated kidney and glomerular growth (229, 231), and reduced the afferent arteriolar dilation and NOS3 fluorescence intensity in arterioles and glomeruli, providing evidence that enhanced NO synthesis by NOS3 in afferent arteriolar and glomerular endothelial cells contributes to diabetic glomerular hypertrophy and hyperfiltration (229). However, other studies provided discrepant results. Renal vasoconstriction and decreases in GFR and RPF in response to l-NAME were similar in diabetic and control animals (235, 256). Finally, a blunted vasoconstriction in response to systemic NOS blockade with l-NMMA (240) and l-NNA (257) was observed in diabetic rats as compared with controls, suggesting a decreased NO-mediated influence. The response of GFR and filtration fraction to l-NMMA was impaired in type 2 diabetic patients compared with controls, indicating that the regulation of glomerular hemodynamics by NO is altered in type 2 diabetes (258). Treatment of STZdiabetic rats for 6 months with a dose of l-NAME that did not raise blood pressure had no effect on GFR, urinary albumin, or NOx excretion (35). More selective NOS inhibitors allowed to elucidate the contribution of individual NOS isoforms in the pathogenesis of diabetic hyperfiltration. NOS1 inhibition with S-methyl-l-thiocitrulline nearly normalized GFR in hyperfiltering diabetic rats (218). Administration of l-imino-ethyl-lysine did not affect blood pressure, GFR, RPF (228), urinary NOx excretion, or kidney weight in diabetic rats (231). These results indicate that NOS1 contributes to altered renal NO production and hemodynamics but do not support a role for increased glomerular activity of NOS2 in experimental diabetes (228, 231).

b. ACEi/ARBs. Two weeks of treatment with quinapril or candesartan normalized UAE, renal NADPH oxidase immunostaining, plasma lipid peroxidation, kidney hydrogen peroxide production in early STZ-diabetes in rats, renal endothelial NOS3 expression, and renal nitrotyrosine expression, suggesting that the increased expression of NADPH oxidase and NOS3, leading to increased nitrooxidative stress, could be involved in the pathology of diabetic kidney disease (232). Imidapril and L-158,809 equally ameliorated the renal up-regulation of lipopolysaccharide-stimulated NOS2 expression of STZ-diabetic rats, suggesting that Ang II activation may play a role in enhanced NOS2 expression in diabetic nephropathy (259). Treatment with perindopril decreased serum ADMA levels in a small number of type 2 diabetic patients (252), suggesting that increased ACE activity may be involved in the endothelial dysfunction associated with ADMA elevation present in patients with noncomplicated type 2 diabetes. c. Antioxidants. In vitro, the effects of high glucose on DDAH activity and ADMA concentrations were reversed by superoxide dismutase (SOD), suggesting that oxidative stress plays a role in the high glucose-induced impairment of DDAH activity (215). The impaired responsiveness of afferent and efferent arterioles from STZ-diabetic rats to l-NNA was reversed by exogenous SOD, indicating that suppressed SOD activity reduces the tonic influence of NO on renal arterioles during the early stage of experimental diabetes (257). d. Inhibitors of AGE formation. One study compared the effects of aminoguanidine with two other inhibitors of NOS, l-NAME and methylguanidine, on the development of experimental diabetic kidney disease (35). Aminoguanidine prevented increases in UAE, urinary NOx, and renal AGE levels, whereas l-NAME and methylguanidine did not, suggesting that the beneficial effects of aminoguanidine may be mediated by decreased AGE formation rather than by NOS inhibition (see also Section II.A). Long-term treatment with aminoguanidine reduced TNF- and NOS2 expression, intraglomerular NOx production, and proteinuria in STZdiabetic rats, providing evidence that the AGE-cytokine-NO sequence pathway could be an important mechanism in the development of diabetic nephropathy (260). e. Anti-VEGF antibodies. Inhibition of VEGF decreased hyperfiltration, glomerular hypertrophy and UAE, and prevented the up-regulation of NOS3 expression in glomerular capillary endothelial cells of STZ-diabetic rats, indicating that NO may be a downstream mediator of VEGF in the kidney (261). 7. Conclusion. In vitro data regarding the NO system are conflicting. Hyperglycemia-induced NO production as well as NO deficiency contribute to ECM accumulation in cell cultures. Renal NOS isoform expression in early experimental diabetes varies considerably between different studies, although the majority reports increased NOS3 expression. In vivo hemodynamic studies that determined GFR and RPF by clearance techniques suggested increased renal NO production/activity in hyperfiltering diabetic rats, whereas studies reporting the contrary used CrCl or other techniques (211).

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Discrepancies may also relate to the absence or presence of insulin treatment. Furthermore, urinary NOx measurements are only an indirect indicator of renal NOS activity. Clinical data support a role for NO in glomerular hyperfiltration in both type 1 and type 2 diabetes. The role of elevated circulating ADMA levels in the pathogenesis of diabetic nephropathy has not been elucidated. Inhibition of NOS and NOS1 by nonselective or more selective l-arginine analogs reduces GFR, giving further support that NOS1 contributes to altered glomerular hemodynamics in diabetes. The effect of NOS blockers on renal vascular resistance is highly discrepant between different studies.

IV. Intracellular Factors A. Diacylglycerol (DAG)-protein kinase C (PKC) pathway

(272). The concomitant increase in total cellular DAG levels (272275) suggests that glucose-induced increases in DAG may contribute to the activation of glomerular PKC observed in early diabetes. In cultured mesangial cells or diabetic glomeruli, hyperglycemia-induced PKC activation has been linked to several abnormalities, i.e., increased arachidonic acid release and production of prostaglandins, increased expression of fibronectin and type 1 (IV) collagen, decreased NaK-ATPase activity (272), stimulation of ERK (273), nuclear factor-B (NF-B) dependent proliferation (276), and suppression of MAPK phospatase-1 (277). PDGF induced de novo synthesis of PKCII and activation of PKC-, -, -, and - in cultured mesangial cells (278). Thus, cytokines can induce PKC activation, but PKC activation also stimulates the expression of cytokines such as VEGF (279) and TGF-1 (272). Overexpression of glucose transporter 1 also led to activation of PKC (81). 4. Experimental evidence for a role of DAG/PKC in diabetic kidney disease. PKC activity was increased in the glomeruli of type 1 diabetic rats from 2 wk after the onset of diabetes (194, 274) until 24 wk of diabetes (52, 272, 280, 281). Concomitant increases in glomerular DAG content have been reported (52, 282). More particularly, PKC was activated in the glomeruli of short-term STZ-diabetic rats as assessed by a change in the subcellular distribution of PKC specific activity (274). However, total PKC activity was not different between glomeruli from control and diabetic rats (274). Twelve weeks of STZ diabetes was associated with activation of the PKC and -I isoforms, as demonstrated by their increased protein expression in the membranous fraction and increased phosphorylation in glomeruli of diabetic rats (272). Furthermore, glomerular PKC activity was also increased in db/db mice compared with nondiabetic control animals (282). PKC activation has been reported to mediate the down-regulation of glomerular low-affinity ET-1 receptors (194). Similar to in vitro studies, PKC activation may contribute to early renal dysfunction in experimental diabetes by the alteration of prostaglandin production and NaK-ATPase activity and the overexpression of TGF-1 and ECM components (272). 5. Clinical evidence for a role of PKC in diabetic kidney disease. In skin fibroblasts cultured in normal and high glucose concentrations, total PKC activity and DAG content were higher in cells from type 1 patients with nephropathy than patients without or control subjects. Recently, a population- and family-based study demonstrated that type 1 diabetic carriers of the T allele of the 1504C/T single nucleotide polymorphism (SNP) or the G allele of the 546C/G SNP in the promoter of PKC-1 gene have an increased risk for diabetic nephropathy compared with type 1 diabetic noncarriers (283). The functional relevance of these SNPs remains to be determined. In monocytes of type 2 diabetic patients, the activity of membrane PKC and the membrane content of the PKCII isoform are acutely regulated by plasma glucose (284). In patients with diabetic nephropathy, the mesangial PKCII expression correlated with serum creatinine, interstitial macrophages, and interstitial fibrosis (285). 6. Agents with effects on DAG/PKC in diabetic kidney disease. The available pharmacological approaches to target PKC include

1. The DAG-PKC system. PKC, a family of serine-threonine kinases, consists of at least 12 structurally related isoforms (262, 263). The classical or conventional PKCs (, I, II, and ) require Ca2 and DAG to become activated, the novel PKCs (, , , , , and ) require only DAG, and the atypical PKCs, namely , , and (the mouse homolog of human PKC) require neither Ca2 nor DAG (262, 264). PKCs participate in signal transduction and intracellular communication in response to specific hormonal, neuronal, and growth factor stimuli. DAG, the major cellular mediator of PKC activation, can be derived from the hydrolysis of phosphoinositol biphosphate to inositol triphosphate or can be formed de novo from glycolytic intermediates (264). PKC isoform activation involves translocation by isozymespecific anchoring proteins, named receptors for activated C-kinase (265). PKC activation leads to changes in vascular permeability, ECM synthesis, smooth muscle contraction, gene expression, cell growth, differentiation, and angiogenesis (264, 266). 2. Expression of DAG/PKC in the normal kidney. The expression of PKC isoforms varies markedly between cells and tissues. The PKC, -I, -II, -, -, -, - isoforms were expressed in normal kidney; PKC was absent; and the expression of the -, -, /-isoforms was unknown (262, 267). However, another study demonstrated PKC, -, -, -, -, -, -, -, -, and - isoforms to be present in preglomerular vessels and glomeruli of normal rat kidney (81, 268). Furthermore, PKC, -I, -II, -, -, and - isoforms were identified by immunoblotting in vascular endothelial cells (269). PKC, -, -, and - were all expressed in rat kidney: PKC in cortical and outer medullary collecting ducts; PKC in thick ascending limbs and inner medullary collecting ducts; PKC and PKC were present in all nephron segments but with a different level of expression (270). In adult kidneys, mesangial cells express PKC and -I, whereas PKCII staining was found only in parietal epithelial cells (81, 271). 3. In vitro evidence for DAG/PKC effects on renal cells. PKC is activated in cultured mesangial cells (272, 273) and in explants of rat glomeruli (274, 275) exposed to elevated glucose concentrations. Hyperglycemia preferentially led to the activation of the PKC and -I isoforms in glomerular cells

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PKC inhibitors, AS-ODNs, and ribozyme inhibition of PKC (263). Staurosporine and several indolocarbazole derivatives are PKC inhibitors with a poor specificity (263). Therefore, in vivo studies have not been feasible until more specific PKC inhibitors were developed. Ruboxistaurin (LY333531) mesylate, a bisindolylmaleimide and highly specific PKCI/II inhibitor, is one of the most promising isoform-selective inhibitors developed to date. Other strategies like vitamin E and thiazolidinediones (TZDs) have also been shown to block PKC activity. a. AS-ODNs. In vitro, AS-ODNs against PKC reduced the high glucose-induced endothelial cell permeability, whereas the control sense and scrambled ODN and the ODN against PKC and - had no effect (286). In vivo, mice injected ip with ODN demonstrated a dose-dependent reduction in PKC mRNA. Studies evaluating the use of AS-ODNs against PKC isoforms for the treatment of diabetes-induced changes in the rat are under way (286).

b. PKC inhibitors. LY333531 decreased the high glucoseinduced PKC activity without changing the increased DAG levels in rat mesangial cells (272). Moreover, in human mesangial cells, LY333531 attenuated PKC activation and normalized the high glucose-induced changes in arachidonic acid release, PGE2 production, and NaK ATPase activity (272). In STZ-diabetic rats, treatment with LY333531 for 2 wk normalized elevated PKC activity in diabetic rat glomeruli, reduced elevated UAE, and normalized the elevated GFR of diabetic rats (281). Treatment with LY333531 for a longer period (12 wk) also normalized the overexpression of TGF1, fibronectin, and collagen 1 (IV) (272). Recently, treatment with LY333531 for 16 wk in db/db mice normalized the increased glomerular PKC activity, reduced the increase in UAE (Fig. 7A) and mesangial area (Fig. 7B), and reduced the overexpression of TGF-1, fibronectin, and type IV collagen (282). In the STZ-diabetic (mRen-2)27 rat, treatment with LY333531 for 6 months attenuated albuminuria, glomerulosclerosis, and, to a lesser extent, tubulointerstitial fibrosis

FIG. 7. A, Effect of PKC inhibition on the UAE rate of nondiabetic db/m and diabetic db/db mice. A 24-h urine sample for each mouse was collected in metabolic cages on 2 consecutive days 16 wk after the start of this experiment. Urine samples were processed to measure urinary albumin concentration using a competitive ELISA. Data were the average of UAE of 2 consecutive days and were shown as mean SD from six to nine mice. Numbers of mice from each group were denoted below each column. *, P 0.05 vs. other group. Quantification of glomerular pathology. Sections stained with periodic acid-Schiff were coded and read by an observer unaware of the experimental protocol. In each animal of four experimental groups, 20 glomeruli cut at the vascular pole were used for morphometric analysis. The extent of increase in mesangial matrix was determined by the presence of periodic acid-Schiff -positive and nuclei-free area in the mesangium. The glomerular area was also traced along the outline of capillary loop using a computer-assisted color image analyzer. Relative glomerular area was shown as the ratio of mesangial area/glomerular area. B, Mesangial area; C, glomerular area; D, relative mesangial area. Numbers of mice from each group are denoted below each column. *, P 0.01 vs. other group. **, P 0.05 vs. db/m and db/m treated with PKC inhibitor. [Reproduced with permission from D. Koya et al.: FASEB J 14:439 447, 2000 (282). The Federation of American Societies for Experimental Biology.]

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(287). In a study in STZ-diabetic rats, LY333531 showed renoprotective effects without effect on any components of the intrarenal TGF- system (288). A clinical trial to evaluate whether LY333531 will be an effective treatment for diabetic nephropathy in combination with ACE inhibition or ARB therapy is ongoing (289). c. Vitamin E. In vitro, vitamin E suppressed DAG accumulation in thrombin-stimulated endothelial cells (290) and prevented the hyperglycemia-induced activation of PKC in VSMC (291) through the activation of DAG kinase (290, 291), which lowers intracellular DAG levels by converting DAG to phosphatidic acid. In STZ-diabetic rats, vitamin E prevented the diabetes-induced increases in DAG and PKC activity in rat glomeruli, normalized glomerular hyperfiltration, and improved UAE, partly through enhancing DAG kinase activity (292). It remains to be determined whether vitamin E directly affects DAG kinase activity or affects it indirectly through its antioxidant effect. d. TZDs. Although the prevention of renal complications by troglitazone (7) and pioglitazone (293) in type 2 diabetic rats is most likely due to their long-term positive effects on the glucose and lipid metabolism, other evidence suggests that TZDs may also have a direct effect on glomerular pathophysiology. In cultured mesangial cells, troglitazone and pioglitazone prevented the high glucose-induced activation of the DAG-PKC pathway activating DAG kinase (273), and troglitazone suppressed the secretion of type I collagen (294). Troglitazone also enhanced DAG kinase activity in glomeruli of diabetic rats and prevented glomerular hyperfiltration and albuminuria without changing blood glucose levels. TZDs are potential therapeutic agents for diabetic nephropathy that may prevent glomerular dysfunction independent of their insulin-sensitizing action through the inhibition of the DAG-PKC-ERK pathway (273). e. Others. Epalrestat abolished the glucose-induced enhancement of PKC activity in cultured mesangial cells (82); aminoguanidine and ramipril prevented the diabetes-associated increase in glomerular PKC activity (49), suggesting a link between the polyol pathway, AGE accumulation, RAS, and the PKC pathway, respectively. 7. Conclusion. In cell cultures and experimental type 1 and type 2 diabetes, hyperglycemia stimulates PKC activity, mostly PKC and PKCI, in a direct way or through an increase in DAG. This PKC activation stimulates prostaglandin, cytokine, and ECM protein production and various signal transduction molecules and decreases NaK-ATPase activity. Preliminary clinical evidence indicates a role for mesangial PKCII in diabetic nephropathy. Selective PKCII inhibition normalized glomerular hyperfiltration, reduced UAE, and decreased glomerular TGF-1 expression and ECM accumulation in experimental diabetes, hence reducing mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis, and loss of renal function. Although these findings clearly implicate a role for PKC in these diabetes-induced changes, the role of other PKC isoforms cannot be excluded.

V. Growth Factors and Cytokines A. Transforming growth factor (TGF-)

1. The TGF- system. The TGF- system belongs to the TGF- superfamily of multifunctional cytokines (295). The three mammalian isoforms, TGF-1, TGF-2, and TGF-3, strongly induce ECM synthesis. TGF-s also contribute to embryonic development, tissue homeostasis, hematopoiesis, angiogenesis, chemotaxis, and immune functions. TGF-s are synthesized and secreted as a latent high-molecular weight complex consisting of mature TGF-, latency-associated peptide, and a latent TGF- binding protein. After proteolytic activation, biologically active TGF-1, TGF-2, and TGF-3 homodimers are most abundantly generated (295). Three TGF- receptors have been identified, i.e., two serine/threonine kinase receptors, TGF- type I receptor (TGF- RI) and TGF- type II receptor (TGF- RII) (296); and TGF- RIII, which facilitates the binding of TGF-s to TGF- RII (295). TGF- signal transduction involves three subclasses of Smad proteins, i.e., receptor-activated (R-Smads), common-partner (Co-Smads) and inhibitory Smads (ISmads), and another pathway, the TGF--activated kinase 1/MAPK signaling pathway (295, 297). Recently, CTGF, a novel fibrogenic protein, has been identified as another downstream mediator of TGF- (298). 2. Expression of TGF- in the normal kidney. The kidney is a site of TGF- production and a target of TGF- action, because both mRNA for all three TGF- isoforms and receptors and the active TGF- proteins have been identified in all cell types of the glomerulus and in proximal tubular cells (299, 300). TGF-1, TGF-2, and TGF-3 differ, however, in their in vivo expression patterns (295). In situ hybridization of rat renal tissue revealed sparse hybridization for TGF-1 mRNA in the tubulointerstitium and a stronger TGF-1 gene expression within proximal tubular cells (301). In mice, the TGF-1 protein was localized in the proximal and distal tubules rather than the glomeruli (302). In rat kidney, podocytes expressed TGF- RIII and very occasionally TGF- RII, but not TGF- RI, whereas all three receptors were constitutively expressed on glomerular endothelial cells (303). CTGF was expressed in cultured mesangial and proximal tubular cells (298, 304). CTGF expression was reported in cortical distal tubules and in medullary and papillary collecting ducts in rat kidney (304), and in glomeruli of mice (298). 3. In vitro evidence for TGF- effects on renal cells. High glucose (305) and glycated albumin (27) stimulated TGF-1 production in cultured mesangial and glomerular endothelial cells. In addition, in cultured mesangial cells, high glucose- or Ang-stimulated matrix protein production was partly mediated by TGF- (306, 307), and TGF- modulated the effect of high glucose on NO production (225). Potential mechanisms for the increased ECM production by TGF-1 in glomerular mesangial, glomerular epithelial, and tubular cells include inhibition of MMP synthesis, stimulation of metalloproteinase inhibitor production, increased expression of PDGF-BioBreeding (BB), CTGF, monocyte chemoattractant protein-1, and regulated upon activation, normal T cell expressed and secreted (RANTES) (298, 308 312). In vitro,

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CTGF induced migration of mesangial cells and increased fibronectin and collagen type I secretion (298, 313). Furthermore, high glucose-induced CTGF mRNA expression and protein secretion in mesangial cells was mediated by TGF-, as shown by its inhibition by an anti-TGF- neutralizing antibody (298). 4. Experimental evidence for a role of TGF- in diabetic kidney disease. In experimental type 1 diabetes, glomerular and tubular TGF-1 mRNA was increased early in the course of diabetes-induced renal changes (301, 314 317). In addition, the increase in glomerular TGF-1 mRNA was sustained in long-term STZ-diabetic rats (300). Recently, the whole intrarenal TGF- system (i.e., TGF-1, TGF-2, and TGF-3 isoforms and TGF- type RI, RII, and RIII receptors) has been studied rigorously in acute and chronic type 1 diabetes, more particular, in STZ-diabetic rats and BB rats, a model of autoimmune type 1 diabetes (299). The TGF-1 and TGF-2 isoforms and the TGF- type RII were the most responsive elements to diabetes induction (299). In the acute phase of STZ diabetes, TGF-1 protein was decreased in the glomerulus but increased in tubules. Glomerular TGF-2 and TGF- type RII protein were up-regulated along with procollagen-1 C-propeptide, a marker for the rate of fibrosis (299). Recently, in db/db mice, in situ hybridization and immunohistochemical staining revealed increases in glomerular and tubular TGF-1 and TGF- RII mRNA and protein when compared with their nondiabetic littermates (302). In OLETF rats, TGF-1 immunostaining was increased compared with Long-Evans Tokushima Otsuka control rats, particularly in interstitial cells and ECM in fibrotic interstitial lesions, and in atrophic or dilated tubular cells, whereas normal tubular cells and glomeruli only stained weakly (318). Another study observed increased kidney TGF-1 mRNA in OLETF rats compared with controls, but TGF-1 immunostaining was different from the previous study, with positive staining especially in the glomerular mesangial area, and weak staining in the tubules (319). Interestingly, administration of recombinant human TGF-2 in normal rats did not induce renal hemodynamic changes, and very little fibrosis was observed (320). CTGF mRNA levels were increased in the renal cortex of STZ-diabetic rats compared with controls, particularly in dilated-appearing proximal tubules, in which it tended to colocalize with IGF-I (304). In the early phase of diabetic kidney disease in db/db mice, when mesangial expansion was mild and interstitial disease and proteinuria were absent, glomerular CTGF expression was increased 27-fold when compared with control mice (298). In whole kidney cortices, a substantially lower elevation of CTGF mRNA was observed, indicating that the primary alteration of CTGF expression was in the glomerulus (298). 5. Clinical evidence for a role of TGF- in diabetic kidney disease. Normoalbuminuric type 1 diabetic patients with a diabetes duration of more than 2 yr had lower serum TGF- levels than control subjects (321). Only 38% of young type 1 diabetics with normo- or microalbuminuria had higher urinary TGF-1 excretion than control subjects (322). The urinary TGF-1 correlated weakly with urinary concentrations of glucose and 1-microglobulin, a marker for tubular dysfunc-

tion, but not with UAE (322). Furthermore, glycemic control did not predict urinary TGF-1 levels in type 1 diabetic subjects (323). The association of urinary TGF-1 excretion with diabetic nephropathy remains controversial (322, 323). Increased TGF- immunostaining has been described in glomeruli and tubulointerstitium of type 1 diabetic subjects with nephropathy (324, 325), but has also been reported in other renal diseases characterized by ECM accumulation (324). Furthermore, a positive correlation between TGF-, fibronectin, and plasminogen activator inhibitor-1 levels in glomeruli and tubulointerstitium was found (324). In normoalbuminuric type 2 diabetic patients, serum TGF- levels were higher than in control subjects irrespective of the diabetes duration (321). In type 2 diabetic patients, an increased renal production of TGF-1 has been shown by measuring aortic, renal vein, and urinary levels of TGF-1 (326). The increased urinary TGF-1 excretion (326 328) correlated with UAE (327) and was associated with severe mesangial expansion (328). However, both renal impairment and diabetes may independently lead to increased urinary TGF-1 levels (329). A higher expression of TGF-1 mRNA was found in glomeruli of type 2 diabetic patients with diabetic nephropathy as compared with normal subjects, and intraglomerular TGF-1 mRNA levels correlated with hemoglobin A1c levels (330). Examination of kidney biopsy specimens for CTGF mRNA by in situ hybridization showed up-regulation of glomerular CTGF mRNA in lesions of diabetic nephropathy. However, this is not specific for diabetic nephropathy because it was also demonstrated in lesions of other renal diseases (331). 6. Agents with effects on the TGF- system in diabetic kidney disease. Several substances are able to inhibit the action of TGF-s, i.e., neutralizing antibodies, AS-ODNs, and dominant negative mutant TGF- receptors. Specific targeting of CTGF is possible with CTGF antibodies and AS-ODNs, but to date no studies have been published regarding the influence of CTGF inhibition in diabetic nephropathy. Other classes of drugs have also been shown to affect the expression of the TGF- system in diabetes, including ACEi, PKC inhibitors, statins, and inhibitors of AGE formation. a. Neutralizing antibodies. In vivo, short-term (9 d) ip administration of a pan-neutralizing TGF- antibody in STZdiabetic mice attenuated the increased renal TGF-1 and TGF- RII mRNA levels and reduced both the diabetesassociated renal/glomerular growth and enhanced renal expression of type IV collagen and fibronectin (332). Systemic treatment for 14 d with recombinant human monoclonal anti-TGF-2 IgG4 (termed CAT-152) in STZ-diabetic rats attenuated the rate of type I collagen synthesis and reduced UAE levels compared with placebo-treated diabetic rats (333). In addition, chronic inhibition of the biological actions of TGF- with a pan-neutralizing monoclonal antibody in db/db mice decreased total plasma TGF-1 levels, attenuated the increase in plasma creatinine concentrations, and substantially attenuated the increase in renal type IV collagen and fibronectin mRNAs, thus preventing glomerulosclerosis (Fig. 8) (334). Interestingly, this study did not find any effect of TGF- antibodies on UAE (334).

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FIG. 8. Kidney matrix gene expression and mesangial matrix expansion in diabetic mice treated with anti-TGF- antibody. Summary of densitometric analyses of 1(IV) collagen/mrpL32 mRNA ratios (A) and fibronectin/ mrpL32 mRNA ratios (B) in the four treatment groups (mean SE; n 8 for each IgG group, and n 9 for each T group). The relative mRNA ratio in the normal-IgG group is assigned a value of 1. *, P 0.05 vs. normal IgG; **, P 0.05 vs. diabetic IgG. Quantitative measurement of extracellular mesangial matrix expansion (C) is expressed as periodic acid-Schiff-positive mesangial material per total glomerular tuft cross-sectional area. An average value was obtained from analyses of 30 glomeruli per mouse. Data are mean SEM; n 8 for each IgG group, and n 9 for each T group. *, P 0.05 vs. normal IgG; **, P 0.05 vs. diabetic IgG. [Reproduced with permission from F. N. Ziyadeh et al.: Proc Natl Acad Sci USA 97:8015 8020, 2000 (334). National Academy of Sciences of the United States of America.]

b. TGF-1 AS-ODNs. In vivo, treatment of STZ-diabetic mice for 10 d with AS-ODNs via osmotic minipumps partially decreased kidney TGF-1 protein levels and prevented the increase in kidney weight and ECM accumulation that were seen in placebo-treated diabetic mice (335). c. ACEi. The effect of ACE inhibition on the intrarenal changes of all three TGF- isoforms and receptors has been examined in experimental type 1 diabetes (336). Enalapril reduced the diabetes-associated renal hypertrophy, albuminuria, and up-regulation of TGF- receptors but had no effect on the glomerular expression of the TGF- isoforms (Fig. 9) (336). Furthermore, in STZ-diabetic rats, administration of ramipril prevented the tubulointerstitial injury and the renal tubular overexpression of TGF-1 and 1 (IV) collagen mRNA (301). In type 1 diabetic patients, captopril treatment for 6 months lowered serum TGF-1 levels. The fall in serum TGF-1 correlated with the ACEi-induced stabilization of GFR over a 2-yr period in patients with overt nephropathy (337). d. PKC inhibition. The specific PKC isoform inhibitor LY333531 abolished the diabetes-associated increases in glo-

merular TGF- mRNA and ECM accumulation when given to STZ-diabetic rats for 3 months (272). In a long-term study in db/db mice, PKC inhibition resulted in the reduction of long-term renal changes, including the increase in glomerular TGF-1 immunostaining (282). e. Statins. Lovastatin suppressed the high glucose-induced up-regulation of TGF-1 and fibronectin mRNA and proteins in cultured rat mesangial cells (338) and suppressed the increase in UAE, kidney weight, glomerular volume, and glomerular TGF-1 mRNA expression in STZ-diabetic rats (338). Simvastatin inhibited CTGF mRNA expression in a concentration-dependent way in cultured human mesangial cells (339). f. AGE inhibition. Long-term treatment with the inhibitor of AGE formation OPB-9195 in OLETF rats normalized the diabetes-associated increases in renal TGF-1 expression and type IV collagen accumulation and decreased albuminuria (319). g. ET receptor antagonists. The mRNA levels of TGF-, PDGF-B, TNF-, basic fibroblast growth factor (bFGF), and

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FIG. 9. Data for procollagen-I C-propeptide (A), TGF-1 mRNA (B), and TGF- type II receptor (TGF-RII) mRNA (C) at d 30 in nondiabetic controls (black bars), placebo-treated diabetic rats (open bars), and enalapriltreated diabetic rats (gray bars). All densitometry in arbitrary units SEM, n 3. *, P 0.05, placebo-treated diabetic rats vs. nondiabetic control rats; **, P 0.05, enalapril-treated diabetic rats vs. placebo-treated diabetic rats. [Reproduced with permission from C. Hill et al.: Diabetologia 44:495500, 2001 (336). Springer.]

of collagen I, III, and IV, laminin B1 and B2 all increased with age in glomeruli of STZ-diabetic rats (192). Twenty-four weeks of treatment with the ETA antagonist FR139317 attenuated the increases in the glomerular mRNA levels of these growth factors and ECM components, attenuated the rise in CrCl, and reduced urinary protein excretion in diabetic rats without any effect of FR139317 in glomeruli of control rats. h. Others. The antioxidant d--tocopherol blocked the high glucose-induced increases in TGF- and matrix accumulation in cultured mesangial cells (340) and prevented the increase in glomerular TGF- immunoreactivity and glomerular size in STZ-diabetic rats (341). The TZD troglitazone prevented not only diabetic glomerular hyperfiltration and albuminuria, but also the increase in mRNA expression of ECM proteins and TGF-1 in glomeruli of diabetic rats (273). Administration of the oral adsorbent AST-120 to OLETF rats attenuated the progression of glomerular sclerosis, tubulointerstitial fibrosis, as well as renal dysfunction. AST-120 reduced the interstitial expression of TGF-1 and tissue inhibitor of metalloproteinase-1 (318). Furthermore, combination therapy of AST-120 and benazepril was more effective than benazepril alone in retarding the progression of interstitial fibrosis by reducing the expression of TGF-1, tissue inhibitor of metalloproteinase-1, and osteopontin (342). 7. Conclusion. In vitro evidence clearly demonstrates that glucose up-regulates TGF- and CTGF, which can induce the expression of ECM proteins. Furthermore, TGF- can also induce ECM production indirectly by stimulating PDGF and chemokines. Compelling evidence demonstrates up-regulation of renal TGF-1, TGF- RII, and CTGF and, to a lesser extent, of TGF-2, in experimental type 1 and type 2 diabetes. Similarly, up-regulation of renal TGF-1 and CTGF and increased urinary TGF-1 excretion have been documented in type 1 and type 2 diabetic patients. The extended experimental and clinical studies indicate that TGF- and CTGF, as

fibrogenic factors, with CTGF acting downstream of TGF-, are important factors in the pathogenesis of diabetic nephropathy, i.e., in mesangial matrix accumulation and in tubulointerstitial fibrosis. Urinary excretion of TGF-1 seemed to correlate with UAE or tubular dysfunction. Inhibition of TGF- by neutralizing antibodies or AS-ODNs attenuated the up-regulation of TGF-1 and reduced renal and glomerular growth and the expression of ECM proteins in experimental type 1 and type 2 diabetes, giving further evidence for a strong pathogenetic role of TGF- in the structural alterations of diabetic kidney disease. The antibodies also reduced UAE in type 1 diabetic and plasma creatinine levels in type 2 diabetic animals, suggesting that TGF- may also play a minor role in diabetic renal dysfunction. Unfortunately, no agents that directly affect the TGF- system exist for clinical use in diabetic patients, and therefore the experimental results cannot be validated in human studies.
B. Growth hormone (GH) and insulin-like growth factors (IGFs)

1. The GH/IGF system. The GH/IGF system consists of a complex family of peptides in the circulation, extracellular space, and in most tissues. GH classically induces IGF-I synthesis in various organs through activation of specific GH receptors (GHRs). Recently, three isoforms of the GHR, i.e., the full-length GHR, GHR-(1279), and GHR-(1277), have been identified in human tissues (343). The GHR signals through receptor-associated Janus-activated kinase 2, signal transducer and activator of transcription proteins, Ras/ MAPK, and phosphatidylinositol-3-kinase. The GHR is down-regulated by internalization and degradation and by phosphatases or suppressors of cytokine signaling proteins (344). The GH binding protein (GHBP) may serve as a circulating buffer/reservoir function for GH, prolong the plasma GH half-life, compete with GH for GHRs, and form unproductive heterodimers with the GHR. The net effect of

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these partly enhancing and partly inhibitory functions on GH action in vivo is complex and difficult to ascertain (345). The IGF system consists of IGF-I and IGF-II, IGF-I receptor (IGFIR), IGF-II/mannose-6-phosphate receptor (IGF-II/man-6PR), IGF binding proteins (IGFBPs), and IGFBP proteases (346). The mitogenic effects of IGF-I on cell growth and metabolism are mediated mainly through the IGF-IR, which binds IGF-I and IGF-II with high affinity (347). The IGF-IIR/ man-6-PR binds IGF-II and mannose-6-phosphate-containing ligands and plays a role in trafficking of lysosomal enzymes (348, 349). In the kidney, GH and IGF-I play a role in renal hemodynamics and in tubular phosphate, sodium, and water absorption (350). IGFs are normally bound to highaffinity IGF binders, IGFBP-1 to IGFBP-6, and several lowaffinity IGF binders, IGFBP-related proteins (IGFBP-rP1 to IGFBP-rP9), and IGFBP proteolytic fragments (346). IGFBPrP2 is identical to CTGF (346) and has been discussed in Section V.A. Circulating IGFBPs may regulate the half-life and endocrine effects of IGFs, whereas cellular IGFBPs may inhibit or stimulate local actions of IGF. The physiological role of the IGFBP-rPs remains to be determined. 2. Expression of GH/IGFs in the normal kidney. The GH/IGF system is expressed in the normal kidney, i.e., GHR and GHBP, IGF-I and IGF-II, the respective IGF-IR and IGF-II/ man-6-PR, and all six specific IGFBPs (343, 345, 346, 348 350). All three GHR isoforms have been discovered in human kidney (343). In rat kidney, GHR mRNA was detected most abundantly in the proximal tubule, less in the medullary thick ascending limb, and not at all in the glomerulus (351), whereas IGF-IR mRNA was concentrated in the medullary thick ascending limb, the distal nephron and collecting duct, and in the glomerulus, with the lowest levels in the proximal tubules (352, 353). IGF-I staining was confined to a few collecting ducts (352). The renal glomerulus is a site of both action and synthesis of IGF-I. Mouse glomerular mesangial cells synthesize and release IGF-I (354), and specific IGF-I receptors are present in cultured glomerular endothelial, epithelial, and mesangial cells (355357), suggesting an autocrine and paracrine action of IGF-I in the kidney. 3. In vitro evidence for GH/IGF effects on renal cells. IGF-I is a potent mitogen for glomerular mesangial cells (355, 358). IGF-I stimulated proteoglycan production (359), as well as the production of laminin, fibronectin, and type IV collagen in mesangial cells (358). Recently, autocrine activation of the IGF-I signaling pathway has been demonstrated in mesangial cells isolated from NOD mice (305). Mesangial cells isolated from obese type 2 diabetic db/db mice exhibited higher levels of IGF-I receptors compared with cells from nondiabetic littermates (360). IGF-I induces NO synthesis and release by cultured vascular endothelial cells through IGF-I receptors (350). 4. Experimental evidence for a role of GH/IGFs in diabetic kidney disease. Experimental evidence for a role of GH/IGFs in the development of diabetic kidney disease is quite extensive (361). Nondiabetic transgenic mice expressing GH, GH releasing factor, or IGF-I, exhibit important glomerular enlargement (362). The GH or GH releasing factor transgenic mice developed glomerulosclerosis, indicating that the mes-

angial changes were in part due to circulating GH (362). Furthermore, glomerular size in GH transgenic mice correlated with UAE and the degree of glomerulosclerosis (363). The STZ-induced diabetic rat, a model of type 1 diabetes, is characterized by low circulating GH concentrations (364), in contrast to findings in humans (365) and STZ-diabetic mice (361). The reason for this discrepancy is still controversial. However, the difference seems to be restricted to GH because similar changes for other elements in the GH/IGF axis have been reported, including low circulating levels of GHBP and IGF-I, alterations in serum IGFBP levels, and specific changes in renal GHBP, IGF receptors, and IGFBPs (361, 364, 366 370). Renal GHBP mRNA expression was increased both in short-term and long-term diabetic rats, but not accompanied by a change in GHR mRNA expression (371). The initial increase in renal growth and function in experimental diabetes was preceded by a rise in renal IGF-I (369, 372), IGFBPs (348, 373), and IGF-II/man-6-PR concentration (374). Furthermore, specific changes occurred in the renal GHBP mRNA, IGF-IR mRNA, and IGFBP mRNA expression in long-term experimental diabetes (368). IGF-I immunostaining increased early in STZ-diabetic rats, in cortical collecting ducts, the thick ascending limbs of the loops of Henle, the macula densa, and some distal convoluted tubules, suggesting that IGF-I is involved in diabetic tubular injury (352). Substantial experimental evidence suggests that exogenous and endogenous IGF-I raises RPF and GFR by reducing renal arteriolar resistance and increasing the glomerular ultrafiltration coefficient, possibly by relaxing the mesangium. These effects of IGF-I on renal hemodynamics are mediated through IGF-I receptors and by induction and release of NO. GH probably does not directly influence renal hemodynamics but increases GFR and RPF through the induction of IGF-I (350). Prepubertal diabetic rats have reduced kidney growth and kidney IGF-I levels compared with adult diabetic rats (375). STZ-diabetic dwarf rats with isolated GH and IGF-I deficiency showed less renal and glomerular hypertrophy and a smaller rise in UAE than diabetic control rats with intact pituitary (376, 377). 5. Clinical evidence for a role of GH/IGFs in diabetic kidney disease. Recently, various clinical studies have been published dealing with possible correlations between serum or urinary GH/IGF-I levels and kidney function in type 1 diabetic patients. Prepubertal microalbuminuric patients had higher levels of urinary GH and urinary and plasma IGF-I than normoalbuminuric diabetic and control subjects (378). Prepubertal and pubertal circulating IGF-I levels were positively correlated to GFR, but not to UAE (378, 379). In adult normoand microalbuminuric patients, urinary IGF-I was strongly correlated to kidney volume, and both urinary IGF-I and GH were positively correlated to microalbuminuria (380). In contrast, no correlations between either plasma GH or IGF-I concentrations and GFR were found in normoalbuminuric type 1 diabetic patients (381). Another study found higher serum GH levels and lower plasma IGF-I levels in type 1 diabetic patients compared with controls, but no correlation between plasma IGF-I and renal function (382). A crosssectional study reported lower IGF-I and IGFBP-3 but higher IGFBP-1 levels in type 1 diabetics compared with type 2

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diabetic patients or controls (383). IGFBP-5 levels were lower in both diabetic groups than in controls, whereas IGFBP-4 levels were similar in diabetics and controls (383). Finally, urinary IGFBP-3 proteolysis correlated with UAE in type 1 and type 2 diabetic subjects (384). Whether induction of IGFBP-3 proteolysis contributes to diabetes-induced renal structural changes by increasing IGF bioavailability is currently unknown (384). 6. Agents with effects on the GH/IGF system in diabetic kidney disease. Various agents have been shown to affect the GH/ IGF axis and exert beneficial renal effects in diabetic kidney disease, including substances that directly target the GH/ IGF axis, such as long-acting somatostatin analogs, specific GHR antagonists, and IGF-I receptor antagonists, and substances that indirectly influence the GH/IGF axis by targeting other systems such as inhibitors of AGE formation and ACEi. a. Long-acting somatostatin analogs. Somatostatin analogs suppress elevated circulating GH levels. In short-term experimental diabetes in the rat, treatment with octreotide from diabetes onset completely inhibited the initial renal hypertrophy and kidney IGF-I accumulation (385), whereas postponed treatment resulted in a partial inhibition of renal hypertrophy (386). Six months of octreotide treatment from the induction of diabetes reduced the increases in kidney weight, renal IGF-I levels, and UAE when compared with untreated rats (387). Octreotide treatment for 3 wk following 3 months of untreated diabetes reduced kidney weight but had no effect on kidney IGF-I levels or UAE. However, the combined treatment of octreotide and captopril reduced both kidney weight and UAE (4). In a type 1 diabetic mouse model, octreotide prevented renal and glomerular growth partly through inhibition of GH hypersecretion and of local kidney IGF-I levels (388). Recently, a new somatostatin analog, PTR3173, blunted renal/glomerular hypertrophy, albuminuria, GFR and renal IGF-I accumulation in NOD mice (389). In clinical studies, acute infusion of octreotide to type 1 diabetic patients reduced RPF, GFR, plasma GH, and glucagon levels (390). In addition, continuous sc octreotide infusion for 12 wk in type 1 diabetic patients reduced elevated GFR and kidney volume (391). b. GHR antagonists. Diabetic GHR antagonist transgenic mice and diabetic GHR/GHBP knockout mice are protected against the development of diabetic renal changes (392394). Furthermore, sc injections of a GHR antagonist, G120K-PEG, for 4 wk normalized the diabetes-associated increases in renal IGF-I accumulation, kidney weight, and glomerular volume and attenuated the diabetes-associated rise in UAE in STZ-diabetic mice and NOD mice without affecting circulating GH and IGF-I levels (Fig. 10) (369, 395). GHR antagonist treatment was equally potent to ACEi treatment in reducing UAE (369). Clinical studies on the effects of this new group of GHR antagonists in diabetic patients may be initiated in the years to come. c. IGF-I receptor antagonists. Treatment with JB3, a peptide analog of IGF-I, for 4 d in STZ-diabetic rats normalized the diabetes-induced increase in kidney weight, kidney protein, and DNA (396).

FIG. 10. Mean glomerular volume (left) and UAE (right) at d 28 in nondiabetic mice treated with placebo (CP) or G120K-PEG (CA) and diabetic mice treated with placebo (DP) or G120K-PEG (DA). Values are means SEM; n 10 in each group. *, P 0.05 vs. all other groups (CP, CA, and DA). , P 0.05 vs. all other groups (CP, CA, and DP). [Reprinted with permission from A. Flyvbjerg et al.: Diabetes 48:377 382, 1999 (369). American Diabetes Association.]

d. ACEi. The possible effects of ACEi on the GH/IGF axis in diabetic kidney disease have not been examined extensively. In a short-term experimental study in STZ-diabetic rats, trandolapril treatment for 1 wk had no effect on kidney IGF-I accumulation or renal enlargement (397). As mentioned above, monotherapy with captopril or octreotide had no effect on renal IGF-I concentrations or UAE, although kidney weight and UAE were reduced with combination therapy (4). e. AGE inhibition. A recent study in long-term STZ-diabetic rats showed the classic changes in the intrarenal IGF axis, with decreased IGF-I and IGFBP-4 and increased IGFBP-1 mRNA expression (398). Administration of aminoguanidine (see also Section II. A) normalized renal IGFBP-1 mRNA expression and partially restored the diabetes-associated changes in IGFBP-4 and IGF-I mRNA (398). 7. Conclusion. Ample in vitro and experimental evidence indicates a role for the GH/IGF-I axis through the complexity of GHR, GHBP, IGFs, IGF receptors, and IGFBPs in both early and late renal changes in experimental diabetes. IGF-I, in particular, seems responsible for the early renal structural and functional changes in diabetic kidney disease, i.e., in renal and glomerular hypertrophy, mesangial hyperplasia, increased UAE and GFR, and tubular injury and growth. Specific changes in the GH/IGF-I system in long-term experimental diabetes seem to involve primarily IGFBPs and receptors. In diabetic patients, in general, circulating GH levels are increased and IGF levels low. A full characterization, however, of the different components of the GH/IGF axis in human diabetic kidney disease awaits future studies. Somatostatin analogs lower circulating GH levels, whereas GHR antagonists prevent functional GHR dimerization and lower circulating concentrations of IGF-I. Despite their different way of action, both treatments had clear beneficial effects on renal and glomerular growth, renal IGF-I accumulation, and UAE in experimental diabetes. In diabetic patients, however, somatostatin analogs mainly reduced the increase in GFR and kidney volume but had no effect on

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UAE. Therefore, clinical use of these agents in the treatment of diabetic kidney disease will depend largely on the outcome of future studies.
C. Vascular endothelial growth factor (VEGF)

1. The VEGF system. The family of VEGFs currently includes VEGF-A, -B, -C, -D, -E, and placenta growth factor (399). VEGF-A, or VEGF, exists as at least six different homodimeric glycoproteins of 121, 145, 165, 183, 189, and 206 amino acids (VEGF121206) in humans and one amino acid shorter in rodents (399, 400). VEGF stimulates endothelial cell proliferation and differentiation, increases vascular permeability, mediates endothelium-dependent vasodilatation, plays a cardinal role in physiological and pathological angiogenesis, and modulates leukocyte kinetics (400, 401). The two best-described VEGF receptors (VEGFR-1 and VEGFR2), also known as fms-like tyrosine kinase 1 and fetal liver kinase 1/KDR, are high-affinity transmembrane tyrosine kinase receptors (400). Soluble fms-like tyrosine kinase, a splice variant of VEGFR-1, regulates VEGF availability by binding VEGF in the circulation (402). Neuropilins serve as isoformspecific coreceptors for VEGF. VEGF production is regulated by several growth factors and cytokines such as TGF-, PDGF, IGF-I (399, 400). VEGF up-regulates the expression of NOS3 in endothelial cells and increases the production of NO (403). 2. Expression of VEGF in the normal kidney. Both VEGF and the two VEGFRs are expressed in the glomeruli and tubules of normal kidney (402, 404 407). Cultured rat and human mesangial cells express both mRNA of VEGF121, VEGF165, and VEGF189 and VEGF protein (407, 408). In rodent and human kidney, VEGF mRNA and/or protein was detected in glomerular podocytes, distal tubules, and collecting ducts, and to a lesser extent in some proximal tubules (402, 404, 406 409). In human glomeruli, variable patterns of VEGF expression were identified, but mostly, all three common isoforms, VEGF121, VEGF165, and VEGF189 were expressed (402). VEGFR-1 and VEGFR-2 were expressed in cultured rat and human mesangial cells (410 412) and cultured rat tubular epithelial cells (413) but not in cultured human podocytes (414). In rat kidney, VEGFR-2 was primarily expressed in glomerular endothelial cells, but also in distal convoluted tubules, collecting ducts and interstitial cells, whereas VEGFR-1 was detected as more diffuse in proximal and distal tubules (404, 413). In human kidney, VEGFR-1 and VEGFR-2 were predominantly localized to preglomerular, glomerular, and postglomerular endothelial cells (405, 406, 411). The expression of VEGFR-1, VEGFR-2, soluble VEGFR-1, and neuropilin-1 in isolated human glomeruli was also heterogenous (402, 414). Neuropilin-1 was detected in whole kidney, single glomeruli, cultured human glomerular podocytes (414), and mesangial cells (410, 411). 3. In vitro evidence for VEGF effects on renal cells. Cultured mesangial cells, glomerular endothelial cells, proximal and distal tubular cells are capable of producing VEGF (415 417). High glucose-induced VEGF production in cultured rat mesangial cells seems to be PKC-dependent (407, 418). AGEs, Ang II, and TGF-1 induced VEGF secretion in cultured

human mesangial cells (408, 416, 417, 419). TGF-1 downregulated VEGFR-2 in vascular endothelial cells (420). In endothelial cells in vitro, VEGF stimulated NF-B concentrations (421) and caused a dose-dependent increase of ACE, suggesting a synergistic relation between VEGF and the RAS (422). In cultured human mesangial cells, VEGF induced proliferation (411) and increased collagen synthesis and p42/ p44 MAPK activity (410). VEGF induced a proliferative and antiapoptotic response in cultured rat tubular epithelial cells (413). Furthermore, murine proximal tubular cells demonstrated augmented de novo protein synthesis and hypertrophy in response to VEGF (423). 4. Experimental evidence for a role of VEGF in diabetic kidney disease. Increased renal expression of VEGF and VEGFRs has been demonstrated in STZ-diabetic rats (404). The increase in VEGF mRNA and protein in glomerular podocytes, distal tubules, and collecting ducts observed after 3 wk of diabetes was sustained until 32 wk of diabetes. In contrast, the early increase in VEGFR-2 mRNA in glomerular and peritubular endothelial cells and interstitial cells, was transient and not observed after 32 wk (404). Early induction of VEGF at the onset of diabetes was also demonstrated in the renal tubular and vascular compartments of STZ-diabetic rats with superimposed hypertension (424) and in genetically diabetic BB rats, with higher amounts of VEGF protein and mRNA than in nondiabetic rats (425). Increased renal VEGF expression has also been described in experimental models of type 2 diabetes (319, 334, 426). In OLETF rats, renal VEGF mRNA and glomerular immunoreactivity were higher than in nondiabetic Long-Evans Tokushima Otsuka rats (319). However, VEGF mRNA expression increased only in the early period of diabetic nephropathy and not further with the duration of diabetes. Positive staining for VEGF was mainly found within the glomeruli (319). In ZDF rats, renal VEGF mRNA levels rose early in the course of diabetes until 7 months (426). At 9 months, when glomerulosclerosis was most pronounced, renal VEGF mRNA levels were reduced (426). In kidneys of db/db mice, VEGF mRNA was increased 2-fold when compared with nondiabetic littermates (334). 5. Clinical evidence for a role of VEGF in diabetic kidney disease. In type 1 diabetic patients, increased (427 429) and unaltered (430, 431) serum or plasma VEGF levels have been found compared with healthy controls. Various studies aimed to correlate circulating VEGF levels to parameters of metabolic control or the severity of diabetic nephropathy. Compared with patients without complications (428, 432) or with microalbuminuria (427), macroalbuminuric patients had higher circulating VEGF levels. However, in other studies, VEGF levels were similar between type 1 diabetics with and without micro- or macroalbuminuria (430, 431, 433). In some studies, correlations were observed between VEGF levels and glycemic control, the severity of diabetic nephropathy or the degree of UAE (427, 428). However, no such correlations were found in other studies (430, 431, 433, 434). Urinary VEGF excretion was not different between patients with diabetic nephropathy and controls (435). Two studies describing VEGF expression in renal biopsy specimens from patients with different kidney diseases included patients

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with diabetic nephropathy (436, 437). Glomerular VEGF expression was highest in the patients with mildest sclerotic changes (436, 437), notably strong in viable glomerular podocytes, and decreased or absent with increasing sclerosis (437). In type 2 diabetic patients, plasma VEGF levels were higher than in controls (438). Plasma VEGF concentration tended to rise with increasing UAE (438); however, no such correlation was reported in other studies (434, 439). In type 2 diabetic patients, plasma VEGF concentration was higher in patients with overt proteinuria than in patients with normo- or microalbuminuria but did not differ between normo- and microalbuminuric patients (407). Urinary VEGF excretion increased with the progression of diabetic nephropathy and correlated weakly with the levels of serum creatinine, CrCl, microalbuminuria, and proteinuria (407). VEGF was up-regulated in glomerular podocytes and distal tubular cells in biopsies with mild diabetic nephropathy, whereas in biopsies with advanced diabetic nephropathy, VEGF expression was decreased or absent in sclerotic glomeruli but extensive in tubules, especially the proximal segment (407). Tubulointerstitial VEGF and VEGF mRNA were lower in type 2 diabetic patients with severe diabetic nephropathy (440). 6. Agents with effects on the VEGF system in diabetic kidney disease. Several VEGF/VEGFR antagonists have been developed, including AS-ODNs, soluble VEGFRs, VEGF aptamers, and ribozymes. In addition, VEGF receptor tyrosine kinase inhibitors, VEGFR-2 antagonists, and peptides that block the interaction of VEGF with its receptors are available. Finally, monoclonal antibodies directed against VEGF or its receptors have been produced. So far, only anti-VEGF antibodies have been used to study the role of VEGF in diabetic kidney disease. a. Neutralizing antibodies. Two studies have investigated the effects of anti-VEGF antibodies in experimental diabetic kidney disease. Treatment for 6 wk in STZ-diabetic rats with a monoclonal neutralizing VEGF antibody abolished the di-

abetes-associated increases in GFR, glomerular hypertrophy, and UAE (Fig. 11) (261). In addition, the diabetes-associated up-regulation of NOS3 expression was prevented. No effect on metabolic control was seen in diabetic animals, and no renal effects were seen in nondiabetic controls (261). Furthermore, VEGF antibody administration in db/db mice attenuated the diabetes-associated increases in kidney weight, glomerular volume, and UAE and abolished the increase in BMT and CrCl. In addition, VEGF antibody tended to reduce the expansion of total mesangial volume (Fig. 12) (441). A role for VEGF in glomerular enlargement was also reported in two nondiabetic models of glomerular hypertrophy. Administration of VEGF antibody in mice fed a high protein diet abolished the glomerular hypertrophy seen in placebotreated animals on an identical diet, without affecting kidney or body weight (442). Similarly, administration of VEGFantibody to uninephrectomized mice reduced the compensatory renal growth and prevented the glomerular hypertrophy (443). b. Receptor inhibitors. VEGFR tyrosine kinase inhibitors (TKi) (444) are newly designed substances, and therefore they have not yet been studied in diabetes. Currently, the effect of VEGFR-TKi on diabetic kidney disease is examined in experimental models of type 1 and type 2 diabetes. c. ACEi. The lack of association between ACE inhibition with lisinopril and circulating plasma VEGF, despite definite effects of these agents on retinopathy and nephropathy (EUCLID study), suggests that these effects are not predominantly mediated by circulating VEGF (433). In contrast, in type 1 diabetic rats, ramipril and perindopril reduced the retinal up-regulation of VEGF as measured by Northern blot analysis and in situ hybridization, respectively (445). d. AGE inhibition. In OLETF rats (319), long-term treatment with OPB-9195 conferred renoprotection and abolished the enhanced renal VEGF immunoreactivity (319).

FIG. 11. A, Albuminuria in untreated (n 12) and antiVEGF Ab-treated (n 7) control rats, and in untreated (n 11), anti-VEGF Ab-treated (n 12), and control Ab-treated (n 9) diabetic rats. *, P 0.0001 vs. control; , P 0.001 vs. diabetes; #, P 0.02 vs. diabetes control Ab; $, P 0.01 vs. control anti-VEGF Ab. B, Glomerular volume in untreated (n 6) and anti-VEGF Ab-treated (n 6) control rats, and in untreated (n 6), anti-VEGF Ab-treated (n 6), and control Ab-treated (n 6) diabetic rats. *, P 0.01 vs. control; , P 0.01 vs. diabetes; #, P 0.001 vs. diabetes control Ab. [Reproduced with permission from A. S. De Vriese et al.: J Am Soc Nephrol 12:9931000, 2001 (261). Lippincott Williams & Wilkins.]

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FIG. 12. BMT and total mesangial volume on d 60 in nondiabetic controls (open bars), placebotreated diabetic db/db mice (black bars), and VEGF-antibody-treated diabetic db/db mice (gray bars). Values are means SEM (n 6 12 in each group). *, P 0.05 vs. nondiabetic controls and VEGF-antibody-treated diabetic db/db mice. [Reproduced with permission from A. Flyvbjerg et al.: Diabetes 51:3090 3094, 2002 (441). American Diabetes Association.]

e. Anti-TGF- antibodies. Anti-TGF- antibodies only slightly prevented the up-regulation of VEGF mRNA in kidneys from db/db mice (334). 7. Conclusion. Substantial studies in type 1 and type 2 diabetic animals and patients consistently demonstrate up-regulation of renal VEGF and VEGFR-2 expression, particularly early in the course of diabetes. The discrepancies in circulating VEGF levels in diabetic patients may reflect differences in sampling and assay methods or timing during the course of diabetic nephropathy. Inhibition of VEGF ameliorated the diabetesassociated renal changes in experimental models, emphasizing a deleterious role for VEGF in the pathogenesis of diabetic nephropathy. Although the cause of the VEGF upregulation in diabetes remains unknown, various factors relevant to the pathogenesis of diabetic nephropathy, including hyperglycemia, AGEs, PKC, Ang II, and TGF-1, are able to stimulate VEGF production in renal cell types. Future research will elucidate the clinical usefulness of VEGF inhibitors in the treatment of diabetic nephropathy.
D. Platelet-derived growth factor (PDGF)

and release a PDGF-like protein (449). In human kidney, PDGF-A is expressed by glomerular podocytes and tubular epithelial cells including collecting duct cells (450), whereas in mouse kidney, PDGF-A is mainly detected in epithelial cells in the loop of Henle and possibly in VSMC (451). PDGF-B is primarily expressed by human mesangial cells (449, 452), rat mesangial cells and podocytes (453, 454). In mouse kidney, however, PDGF-B is predominantly expressed by vascular endothelial cells and minimally by glomerular podocytes (451). PDGF-C is constitutively expressed by arterial smooth muscle cells and collecting duct cells in rat kidney (455). PDGF-D is expressed by glomerular podocytes and VSMCs of mature human kidney (447). In human and mouse kidney, PDGFR- is extensively expressed by interstitial cells, and occasionally by human mesangial cells and VSMCs (451, 456, 457), whereas PDGFR- is primarily expressed by mesangial cells, interstitial cells, and VSMCs (447, 451, 452, 457). In rat kidney, PDGFR- is weakly expressed by interstitial cells (451), mesangial cells, and podocytes (454). Thus, the patterns of renal expression of PDGF and its receptors differ slightly between different species. 3. In vitro evidence for PDGF effects on renal cells. Exposure to high glucose increased PDGF-B mRNA expression in cultured human mesangial cells (458) and caused changes in cell growth, collagen synthesis, and PDGF secretion in cultured human proximal tubular cells (459). Furthermore, high glucose increased PDGFR- in rat mesangial and human capillary endothelial cells through PKC activation (460). Glucose seemed to lower the threshold at which PDGF stimulates TGF-1 synthesis in cultured proximal tubular cells (461). The AGE-induced release of TGF- and production of collagens in cultured mesangial cells were mediated via PDGF (24, 462). PDGF increased RNA and protein synthesis (357) and SPARC mRNA levels (463); activated specific PKC isoforms, namely PKC, -I, -, and - in cultured mesangial cells (278); and induced mesangial cell proliferation and migration (464). 4. Experimental evidence for a role of PDGF in diabetic kidney disease. In short-term STZ-diabetic rats, PDGF-B and PDGFR- protein expression was enhanced in glomerular podocytes and mesangial cells compared with control or insulin-treated diabetic rats (454). Even very early after the onset of STZ diabetes, PDGF B-mRNA and PDGF-B immunostaining were slightly increased, preceding mesangial proliferation, increased TGF-1 expression, and ECM deposition

1. The PDGF system. The PDGF family consists of two structurally similar A- and B-polypeptide chains (PDGF-A and PDGF-B) that are able to form three disulfide-bonded homoand heterodimers, i.e., PDGF-AA, PDGF-BB, and PDGF-AB (446). PDGF-C and PDGF-D are novel growth factors belonging to the PDGF family (447, 448). Soluble PDGF binding proteins such as 2-macroglobulin, PDGF-associated protein, and the extracellular part of the PDGF- receptor as well as ECM components such as secreted protein acidic and rich in cysteine (SPARC) regulate the activity and availability of PDGF isoforms (446). PDGF is synthesized by many different cell types. PDGF isoforms exert their paracrine or autocrine effects by activating two tyrosine kinase receptors, PDGF receptor (PDGFR)- and PDGFR-, which require ligandinduced dimerization for their activation. PDGF-AA induces -receptor dimerization, PDGF-AB induces - or receptor dimerization, and PDGF-BB induces all three dimeric combinations of - and -receptors (446). PDGF has potent mitogenic and weak angiogenic effects, modulates chemotaxis, blood vessel tonus, and platelet aggregation, and is involved in tissue homeostasis (446). 2. Expression of PDGF in the normal kidney. Cultured human mesangial cells express both PDGF-A and -B chain mRNA

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(465). In NOD mice, however, PDGF-B mRNA levels in microdissected glomeruli were unaltered (316). Long-term STZ diabetes was associated with elevated PDGF-B mRNA expression in glomeruli and tubulointerstitium (300, 466), whereas PDGF-A mRNA levels were not altered (300). Insulin treatment partially ameliorated the increase in PDGF-B mRNA in glomeruli of diabetic rats (300). In type 1 diabetic rats, a reduction in SPARC mRNA and protein has been associated with early diabetes-associated kidney growth (467). Administration of PDGF to Goto-Kakizaki rats, a model of lean type 2 diabetes, led to acute mesangial cell proliferation and activation but had no long-term effects on kidney structure or function (468). In disagreement with the in vitro findings, repeated injections of AGEs in normal mice led to an increase in the expression of type IV collagen and laminin genes in the glomeruli, and was accompanied by up-regulation of TGF-1, but not PDGF-B expression (36). 5. Clinical evidence for a role of PDGF in diabetic kidney disease. Clinical evidence for a role of PDGF in the pathogenesis of diabetic kidney disease is very limited. Serum PDGF levels did not differ between type 1 and type 2 diabetic patients without albuminuria, but the serum PDGF levels of all the diabetic patients were increased compared with agematched controls and correlated negatively with serum creatinine levels (469). Long-term type 1 diabetic patients had a higher urinary excretion of PDGF-BB than controls (470). Urinary excretion of PDGF was elevated in all diabetic subgroups, but the excretion of PDGF was higher in patients with micro- or macroalbuminuria than with normoalbuminuria, although there was a considerable overlap between the groups (470). Platelet -thromboglobulin content and PDGF were markedly decreased in 10 type 1 diabetic patients, suggesting that PDGF release might be increased in diabetic subjects (471). In a study in type 2 diabetic patients, elevated serum SPARC concentrations were detected in patients with severe tubulointerstitial lesions associated with and without advanced glomerular lesions (472). In renal biopsies from type 2 diabetic patients with overt diabetic nephropathy, PDGF-A and PDGF-B mRNA expression was up-regulated compared with control tissue (473). In addition, immunohistochemistry showed abundant expression of PDGF-A and PDGF-B in glomeruli and the tubulointerstitial compartment, whereas only minimal immunoreactive PDGF-A and PDGF-B was detected in control tissue. PDGF-A immunostaining was localized to glomerular and tubulointerstitial epithelial cells, but PDGF-B immunostaining was predominantly extracellular and localized to areas of fibrosis, suggesting that PDGF-B may be sequestered in the ECM (473). 6. Agents with effects on the PDGF system in diabetic kidney disease. Several agents inhibit the effects of PDGF by binding PDGF or by blocking the PDGFRs, i.e., oligonucleotide aptamers, low-molecular weight molecules, soluble PDGFRs, polyclonal antibodies or monoclonal PDGFR antibodies and several PDGFR-TKi. Few substances, however, have been used to investigate the role of PDGF in diabetes. Various drugs with well-known or potential therapeutic effects on diabetic kidney disease, such as ACEi, PKC inhibitors, AGE inhibitors, and ET receptor antagonists may also modulate renal PDGF expression.

a. Neutralizing antibodies. A polyclonal goat antibody, which recognizes all three dimeric forms of PDGF, abrogated the AGE-induced increase in type IV collagen mRNA in mouse mesangial cells cultured in normal glucose, suggesting that PDGF is an intermediate factor in the AGE-induced increase in ECM (24). b. PDGFR-TKi. In cultured mesangial cells, STI 571, a receptor tyrosine kinase inhibitor of the class of the 2phenylaminopyridines, reduced the PDGF-stimulated mesangial proliferation in a dose-dependent manner (474). c. ACEi. Ramipril reduced the fetal calf serum activated mesangial cell proliferation and PDGF-A and -B expression (475) and completely abolished the PKC-induced PDGF-A and -B expression, which may be independent of its ability to inhibit ACE and could represent an additional mechanism in the renal protective effects of this ACEi (475). In contrast, treatment of STZ-diabetic rats with enalapril for 24 wk reduced CrCl and urinary protein excretion, produced a nonsignificant reduction in blood pressure, but had no effect on the increased glomerular mRNA levels of PDGF-B, TNF-, TGF-, and bFGF, although it attenuated the increase in glomerular ET-1 expression (476). d. PKC inhibition. The PKC inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, staurosporine, and PKC inhibitor peptide, inhibited the PDGF-induced cellular proliferation and ET-1 secretion in cultured rat mesangial cells (477). e. Statins. Simvastatin inhibited PDGF-induced DNA synthesis in human glomerular mesangial cells in a dosedependent manner (478), providing evidence that statins may ameliorate glomerular pathology, at least in part, by a direct cellular effect and not only by their cholesterol-lowering potential. f. ET receptor antagonists. The mRNA levels of ECM components including 1(I), 1(III), and 1(IV) collagen; laminin B1 and B2; and growth factors including PDGF-B, TNF-, TGF-, and bFGF all increased with age in glomeruli of STZ-diabetic rats (192). Treatment for 24 wk with the specific ET receptor A antagonist FR139317 attenuated the increases in the glomerular mRNA levels of these growth factors and ECM components, attenuated the rise in CrCl, and reduced urinary protein excretion in diabetic rats, but did not affect blood pressure. g. Others. Aminoguanidine administration during 6 months attenuated the overexpression of PDGF-B mRNA in renal tubules and glomeruli of STZ-diabetic rats (466). Trapidil, an antiplatelet drug that competitively inhibits the binding of PDGF-BB to PDGFR-, inhibited PDGF-induced mesangial cell proliferation in vitro (479). In STZ-diabetic rats, daily ip injections with trapidil for 4 wk prevented glomerular hypertrophy (Fig. 13) (454). 7. Conclusion. In vitro and experimental data implicate the up-regulation of PDGF-B and PDGFR- and down-regulation of SPARC in glomeruli and tubulointerstitium in the early diabetes-associated renal hypertrophy. Furthermore,

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AGEs increase PDGF expression in vitro, but not in vivo. PDGF can stimulate ECM formation, PKC activation, and SPARC expression in cultured mesangial cells and mesangial cell proliferation both in vitro and in vivo. Diabetic patients have increased serum PDGF levels and increased urinary PDGF excretion. Overt diabetic nephropathy is associated with renal overexpression of PDGF. Trapidil, a nonspecific PDGF inhibitor, prevents glomerular hypertrophy in experimental diabetes in addition to inhibition of mesangial cell proliferation, giving further support for PDGF as a mediator of renal/glomerular growth. Future studies are warranted to explore the potential benefit of specific PDGF inhibitors in experimental diabetic kidney disease because, so far, neutralizing antibodies and PDGFR-TKi have only been investigated in cultured mesangial cells.

VI. Outlook and Future Perspectives

Tight metabolic and antihypertensive controls remain cornerstone interventions in the treatment of micro- and macrovascular complications in type 1 and type 2 diabetes. However, vascular diabetic complications, including diabetic nephropathy, remain a huge clinical problem despite implementation of overall intensified glycemic and antihypertensive control in these patients. Accordingly, there is an ongoing need for development of new therapeutic strategies in the treatment of kidney disease, which may imply that combined intervention is required toward various pathways of importance in the development of diabetic nephropathy. As described in the present review, extensive research during recent years has identified several new pathways

FIG. 13. A, Glomerular volume of control, diabetic, and insulin-treated diabetic rats. Glomerular volume in diabetic rats (closed bar) was higher than in the control rats (open bar) at all time points. Glomerular volume in diabetic rats treated with insulin (shaded bar) was lower than in the diabetic groups at 4 and 12 wk. Results were expressed as mean SD. *, P 0.05; **, P 0.01 vs. control; ##, P 0.01 vs. diabetic. C2, C4, and C12, Control rats at wk 2, 4, and 12; D2, D4, and D12, diabetic rats at wk 2, 4, and 12; DI4 and DI12, insulin-treated diabetic rats at wk 4 and 12. B, The effect of the inhibition of enhanced PDGF system on glomerular hypertrophy in diabetic rats. Glomerular volume in diabetic rats (closed bar) was higher than in the control rats (open bar), and in diabetic rats treated with trapidil (shaded bar) at 4 wk. Results were expressed as mean SD. **, P 0.01 vs. control; ##, P 0.001 vs. diabetic. C4, Control rats at 4 wk; D4, diabetic rats at 4 wk; DT4, trapidil-treated rats at 4 wk. [Reproduced with permission from H. Nakagawa et al.: Diabetes Res Clin Pract 48:8798, 2000 (454). Elsevier.]

FIG. 14. Schematic illustration of the potential hierarchy and interactions between metabolic, hemodynamic, and intracellular factors and growth factors/cytokines in the pathophysiology of diabetic kidney disease.

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Schrijvers et al. Factors Influencing Diabetic Nephropathy sawa K, Kawata T, Koike T 1997 Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 46:895 899 Zheng F, He C, Cai W, Hattori M, Steffes M, Vlassara H 2002 Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products. Diabetes Metab Res Rev 18:224 237 Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, DAgati VD, Schmidt AM 2003 RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:11231137 Campbell J, Davidson IWF, Lei HP 1950 The production of permanent diabetes by highly purified growth hormone. Endocrinology 46:588 590 Lundbk K, Christensen NJ, Jensen VA, Johansen K, Olsen TS, Hansen AP, rskov H, sterby R 1970 Diabetes, diabetic angiopathy, and growth hormone. Lancet 2:131133 Yde H 1969 The growth hormone dependent sulfation factor in serum from patients with various types of diabetes. Acta Med Scand 186:293297 Wendt T, Tanji N, Guo J, Hudson BI, Bierhaus A, Ramasamy R, Arnold B, Nawroth PP, Yan SF, DAgati V, Schmidt AM 2003 Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 14:13831395 Williams ME 2003 New therapies for advanced glycation end product nephrotoxicity: current challenges. Am J Kidney Dis 41: S42S47 Vlassara H, Palace MR 2002 Diabetes and advanced glycation endproducts. J Intern Med 251:87101 Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, Strihou CY, Monnier VM, Witztum JL, Kurokawa K 1997 Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 100:29953004 Niwa T, Katsuzaki T, Miyazaki S, Miyazaki T, Ishizaki Y, Hayase F, Tatemichi N, Takei Y 1997 Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients. J Clin Invest 99:12721280 Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, DAgati VD 2000 Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 11:1656 1666 Soulis T, Cooper ME, Vranes D, Bucala R, Jerums G 1996 Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney Int 50:627 634 Soulis T, Thallas V, Youssef S, Gilbert RE, McWilliam BG, Murray-McIntosh RP, Cooper ME 1997 Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury. Diabetologia 40:619 628 Huang Y, Lin S, Zhou J 1998 Gene expression of receptor for advanced glycosylation end products and its modulation by aminoguanidine in diabetic kidney tissue. Chin Med J (Engl) 111: 698 704 He CJ, Zheng F, Stitt A, Striker L, Hattori M, Vlassara H 2000 Differential expression of renal AGE-receptor genes in NOD mice: possible role in nonobese diabetic renal disease. Kidney Int 58: 19311940 Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ 1992 Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA 89:28732877 Skolnik EY, Yang Z, Makita Z, Radoff S, Kirstein M, Vlassara H 1991 Human and rat mesangial cell receptors for glucose-modified proteins: potential role in kidney tissue remodelling and diabetic nephropathy. J Exp Med 174:931939 Youssef S, Nguyen DT, Soulis T, Panagiotopoulos S, Jerums G, Cooper ME 1999 Effect of diabetes and aminoguanidine therapy on

with impact on the development of diabetic kidney disease. Accordingly, many potential strategies to prevent the development or retard the progression of diabetic nephropathy, independently of metabolic control and hypertension, are currently under evaluation. The challenge for future research will be to unravel these complex interactions between hyperglycemia, metabolic factors (e.g., AGE- and AR/polyol pathways), hemodynamic factors (e.g., AngII/RAS-, ET-, and NO-pathways), intracellular factors (e.g., DAG-PKC, NF-B, and MAPK), and growth factors/cytokines (e.g., TGF-, CTGF, GH, IGF, VEGF, and PDGF), which may lead to a better understanding of the pathogenesis of diabetic kidney disease. A schematic illustration of the potential hierarchy and interactions between these different systems is given in Fig. 14. The future search for new potential pathways and the development of rational strategies for improved management of diabetic nephropathy may be facilitated by the use of newly developed tools like microarray technology, glycomics, and proteomics.
Acknowledgments

9. 10.

11. 12. 13. 14.

15. Address all correspondence and requests for reprints to: Allan Flyvbjerg, M.D., D.M.Sc., Medical Department M/Medical Research Laboratories, Clinical Institute, Aarhus University Hospital, Nrrebrogade 44, DK-8000 Aarhus C, Denmark. E-mail: allan.flyvbjerg@dadlnet.dk This work was supported by the Danish Diabetes Association, the Danish Medical Research Council (Grant 9700592), the Eva and Henry Frnkels Memorial Foundation, the Nordic Insulin Foundation, the Institute of Experimental Clinical Research, University of Aarhus, Denmark, the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT), and the Fund for Scientific ResearchFlanders. Due to space limitations, many important contributions could not be referenced. 16. 17.

18.

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