Kidney International, Vol. 65 (2004), pp.
2003–2017
The role of vascular endothelial growth factor (VEGF) in renal
pathophysiology
BIEKE F. SCHRIJVERS, ALLAN FLYVBJERG, and AN S. DE VRIESE
Renal Unit, Department of Internal Medicine, Gent University Hospital, Gent, Belgium; Medical Department M (Diabetes and
Endocrinology), Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus,
Denmark; and Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, Brugge, Belgium
The role of vascular endothelial growth factor (VEGF) in renal
pathophysiology. Vascular endothelial growth factor (VEGF)
is an endothelial-specific growth factor that promotes endothe-
lial cell proliferation, differentiation and survival, mediates
endothelium-dependent vasodilatation, induces microvascular
hyperpermeability and participates in interstitial matrix re-
modeling. In the kidney, VEGF expression is most promi-
nent in glomerular podocytes and in tubular epithelial cells,
while VEGF receptors are mainly found on preglomerular,
glomerular, and peritubular endothelial cells. The role of VEGF
in normal renal physiology is essentially unknown. The ab-
sence of prominent effects of VEGF blockade in normal
experimental animals suggests a limited function during home-
ostasis, although a role in the formation and maintenance of
glomerular capillary endothelial fenestrations has been sug-
gested. VEGF and its receptors are up-regulated in experi-
mental animals and humans with type 1 and type 2 diabetes.
Inhibition of VEGF has beneficial effects on diabetes-induced
functional and structural alterations, suggesting a deleterious
role for VEGF in the pathophysiology of diabetic nephropa-
thy. VEGF is required for glomerular and tubular hypertro-
phy and proliferation in response to nephron reduction, and
loss of VEGF is associated with the development of glomeru-
losclerosis and tubulointerstitial fibrosis in the remnant kidney.
No firm conclusions on the role of VEGF in minimal change
or membranous glomerulonephritis can be drawn. VEGF may
be an essential mediator of glomerular recovery in prolif-
erative glomerulonephritis. Glomerular and tubulointerstitial
repair in thrombotic microangiopathy and cyclosporin nephro-
toxicity may also be VEGF-dependent. In conclusion, VEGF
is required for growth and proliferation of glomerular and per-
itubular endothelial cells. While deleterious in some, it may con-
tribute to recovery in other forms of renal diseases.
Key words: compensatory hypertrophy, diabetic nephropathy, glomeru-
lonephritis, transplant rejection, vascular endothelial growth factor
(VEGF), uremia.
Received for publication April 24, 2003
and in revised form August 7, 2003, and September 25, 2003
Accepted for publication December 3, 2003


C 2004 by the International Society of Nephrology
2003
PERSPECTIVES IN BASIC SCIENCE
Vascular endothelial growth factor (VEGF-A or
VEGF), formerly called vasculotropin or vascular per-
meability factor (VPF), belongs to a family of multipo-
tent cytokines, also including VEGF-B, -C, -D, -E, and
placenta growth factor [1]. Alternative exon splicing of a
single VEGF gene results in at least six different isoforms.
They are homodimeric glycoproteins of 121, 145, 165,
183, 189, and 206 amino acids (VEGF 121−206 ) in humans
and are one amino acid shorter in rodents [2]. VEGF 121 ,
VEGF 165 , and VEGF 189 are the most abundantly ex-
pressed isoforms, whereas VEGF 145 and VEGF 206 are
comparatively rare [2]. VEGF stimulates endothelial
cell proliferation and differentiation, increases vascular
permeability, mediates endothelium-dependent vasodi-
latation, and supports vascular survival by preventing
endothelial apoptosis [1, 2]. In addition, VEGF induces
plasminogen activator, plasminogen activator inhibitor-
1 and interstitial collagenase, factors important in
matrix remodeling. Furthermore, VEGF promotes
monocyte chemotaxis and expression of adhesion
molecules [1, 2]. VEGF 165 , VEGF 189 , and VEGF 121 differ
in affinity for heparin and heparan-sulfate proteoglycans
(VEGF 189 > VEGF 165 > VEGF 121 ) and in mitogenic ef-
fect (VEGF 165 > VEGF 121 ) [2]. VEGF 165 , VEGF 189 , and
VEGF 206 are in most part sequestered in the extracellu-
lar matrix and at the cell surface, whereas VEGF 121 and
VEGF 145 are freely released [2]. The receptors for VEGF,
previously described as fms-like tyrosine kinase (Flt-1)
and fetal liver kinase 1 (Flk-1/KDR), now designated as
VEGFR-1 and VEGFR-2, respectively, are high-affinity
transmembrane tyrosine kinase receptors [2]. Soluble
VEGFR-1 (sVEGFR-1), a splice variant of VEGFR-1,
regulates VEGF availability by binding VEGF in the cir-
culation [3, 4]. Neuropilin-1 and Neuropilin-2 act as iso-
form specific co-receptors for VEGF [5]. Hypoxia is the
main stimulus for VEGF expression and/or production.
Several growth factors and cytokines such as epidermal
growth factor, transforming growth factor b (TGF-b),
platelet-derived growth factor (PDGF), insulin-like
growth factor I (IGF-I), angiotensin II, interleukin-1
2004 Schrijvers et al: VEGF in renal pathophysiology
(IL-1), and IL-6 also have the potential to up-regulate
VEGF expression. VEGF may be induced by other fac-
tors as well [i.e., prostaglandins, mechanical stress, hy-
perglycemia, advanced glycation end products (AGEs),
protein kinase C (PKC), and reactive oxygen species
(ROS)]. VEGF up-regulates the expression of endothe-
lial nitric oxide synthase (NOS3) in endothelial cells and
increases the production of nitric oxide [6]. Several lines
of evidence have indicated that VEGF exerts its biologic
effects through nitric oxide [7]. Nitric oxide may down-
regulate VEGF expression and thus function in a negative
feedback regulator mechanism [8]. Recently, 15 differ-
ent sequence polymorphisms have been identified within
the VEGF gene, including a C/T base change at position
−460, a G/C change at +405 and a A/C change at −141
[9]. The −460C/+405G and −460T/+405C haplotypes are
the most frequently observed in the normal population
[9]. A correlation of the +405 genotype with production
of VEGF has been demonstrated in vitro [9] and in vivo
[10], with the highest VEGF production for the GG geno-
type, intermediate production for the GC genotype and
lowest production for the CC genotype [9]. Further, the
combination of the +405G genotype with other polymor-
phisms resulted in higher VEGF promotor activity [11].
A deletion/insertion (D/I) polymorphism at the −2549
position of the VEGF promotor region has been linked
to increased transcriptional activity [12].
Angiopoietins form another family of endothelial-
specific growth factors consisting of angiopoietin-1
(Ang-1) and angiopoietin-2 (Ang-2), which bind to tyro-
sine kinase receptors Tie1 and Tie2 [13]. Angiopoietins
and VEGF play co-ordinated and complementary roles
in vascular homeostasis [13]. Ang-2 stimulates new blood
vessel formation in the presence of VEGF, but promotes
endothelial apoptosis and vessel regression when VEGF
levels are low [14].
VEGF IN RENAL PHYSIOLOGY
This section elaborates on the expression and the po-
tential role of VEGF, angiopoietins, and their receptors
in the normal adult kidney. A comprehensive discussion
of the role of the VEGF system in renal development
is beyond the scope and space limitations of this re-
view and has been published elsewhere [15]. Cultured
rat and human mesangial cells express both mRNA of
VEGF 121 , VEGF 165 , and VEGF 189 , and VEGF protein
[16, 17]. In rodent and human kidneys, VEGF mRNA
and/or protein were detected predominantly in glomeru-
lar podocytes, distal tubules, and collecting ducts, and to
a lesser extent in some proximal tubules [3, 16, 18–23].
The expression of the different VEGF isoforms in normal
human glomeruli was complex and variable with substan-
tial inter- and intraindividual variation [3]. Ang-1, but not
Ang-2, was identified in adult human glomeruli, partic-
ularly in podocytes [24]. VEGFR-1 and VEGFR-2 were
detected in cultured rat and human mesangial cells [25–
28] and in cultured rat renal tubular epithelial cells [29],
but not in cultured primary human podocytes [30]. In con-
trast, conditionally immortalized human podocytes ex-
pressed VEGFR-1, VEGFR-3 and Neuropilin-1 but not
VEGFR-2 [31]. Cultured mouse glomerular endothelial
cells and transformed tubular epithelial cells expressed
Neuropilin-1 and Neuropilin-2 [32]. Neuropilin-1 was
also detected in cultured human mesangial cells [25, 27]
and in cultured primary human glomerular podocytes
[30]. The expression of VEGFR-1, VEGFR-2, sVEGFR-
1, and Neuropilin-1 in isolated human glomeruli was
also heterogenous [3, 30]. In human kidney, VEGFR-1
and VEGFR-2 were predominantly expressed on pre-
glomerular, glomerular, and peritubular endothelial cells
[20, 23, 27, 33]. In rat kidney, VEGFR-2 expression was
detected in glomerular and peritubular endothelial cells,
in distal convoluted tubules and collecting ducts, and
in cortical interstitial fibroblast and medullary intersti-
tial cells, whereas VEGFR-1 was expressed more diffuse
in proximal and distal tubules [19, 29]. In human kid-
ney, Neuropilin-1 was detected in glomerular podocytes
[30]. Neuropilin-1 and Neuropilin-2 were localized in per-
itubular capillary endothelial cells in adult mouse and rat
kidney [32]. Tie2 was demonstrated in glomerular cap-
illary endothelial cells of human and rat glomeruli and
in cultured human microvascular endothelial cells [24].
In summary, in vivo, capillary endothelial cells express
VEGFR-1, VEGFR-2, and Tie2, glomerular podocytes
express Neuropilin-1 and produce VEGF and Ang-1.
Although the functions of constitutively expressed
VEGF and VEGF receptors in the normal kidney are
largely unknown, some hypotheses may be derived from
the peculiar distribution of the molecule and its recep-
tors in the kidney. VEGF is strongly expressed by vis-
ceral epithelial cells while its binding sites are localized
on glomerular endothelial cells. If one assumes the ex-
istence of a paracrine loop in the glomerulus, VEGF
must move in the opposite direction of the glomerular
filtrate in order to bind to its receptors. The presence
of such complex mechanism suggests that the strategic
localization of podocytes is required for the correct sens-
ing and interpretation of the stimulus for VEGF release.
VEGF may be involved in the induction and maintenance
of the fenestrae in glomerular capillary endothelial cells
[37]. Given the role of VEGF in promoting microvascu-
lar permeability, it has been speculated that VEGF may
regulate glomerular permeability, although it is generally
acknowledged that the capillary fenestrations do not rep-
resent the ultimate barrier to filtration. Recently, in vitro
evidence indicated that VEGF may act as an autocrine
factor on calcium homeostasis and cell survival in human
podocytes [31]. In contrast to the prominent expression of
the VEGF system in the adult kidney, the administration
 Schrijvers et al: VEGF in renal pathophysiology
or inhibition of VEGF in normal adult animals appears to
have only minimal effects. In the isolated perfused rat kid-
ney, administration of VEGF increased the renal blood
flow but did not influence the glomerular filtration rate or
the permselectivity of the glomerular barrier wall [34]. In
vivo infusions of VEGF into the renal artery of rats did
not influence protein excretion rate [34]. The administra-
tion of neutralizing monoclonal anti-VEGF-antibodies to
normal rats had no effect on glomerular filtration rate or
glomerular volume [35]. Injection of a VEGF 165 aptamer,
an oligonucleotide-based VEGF 165 antagonist, in normal
rats had no effect on kidney and glomerular morphology,
did not induce proteinuria and did not affect glomerular
cell proliferation and the number of endothelial fenes-
trations [36]. In contrast, podocyte-specific heterozygous
and homozygous deletions of VEGF in mice resulted in
proteinuria and endotheliosis by 21/2 weeks of age, and
in perinatal lethality, respectively, with loss of endothelial
fenestrations or failure to form fenestrations [37]. Con-
versely, podocyte-specific overexpression of VEGF 165 led
to a collapsing glomerulopathy [37].
VEGF IN RENAL PATHOPHYSIOLOGY
Diabetic nephropathy
Type 1 diabetes. VEGF mRNA and protein expres-
sion were increased at the onset of diabetes in genetically
diabetic BioBreeding rats [38], in glomerular podocytes,
distal tubules and collecting ducts after 3 weeks and 32
weeks of streptozotocin (STZ)-diabetes in rats [19] and in
renal tubular and vascular compartments in STZ-diabetic
rats with superimposed hypertension [39]. More specifi-
cally, the VEGF 164 and VEGF 188 isoforms increased af-
ter STZ-diabetes induction which was reversed by insulin
treatment [40]. Glomerular VEGFR-1 and VEGFR-2
mRNA expression were higher after 6 weeks of STZ-
diabetes [40]. Similarly, VEGFR-2 mRNA was increased
in glomerular and peritubular endothelial cells and inter-
stitial cells after 3 weeks of STZ-diabetes but not after
32 weeks [19]. To assess the role of VEGF in the patho-
physiology of early renal dysfunction in diabetes, type 1
diabetic rats were treated with monoclonal neutralizing
anti-VEGF-antibodies for 6 weeks. Inhibition of VEGF
abolished the diabetes-associated glomerular hyperfiltra-
tion, glomerular hypertrophy, and urinary albumin ex-
cretion (UAE) without an effect on metabolic control
[35]. In addition, the diabetes-associated up-regulation
of NOS3 expression was prevented, further supporting
the evidence that nitric oxide acts as a downstream me-
diator of VEGF [35].
Both increased [abstract; Abdel Aziz MY, Nephrol
Dial Transplant 12:1538a, 1997] [41, 42] and unaltered
[43, 44] serum or plasma VEGF levels were observed
in type 1 diabetic patients versus control subjects. Var-
ious studies examined a correlation between circulat-
2005
ing VEGF levels and parameters reflecting the sever-
ity of diabetic nephropathy. VEGF levels were higher
in macroalbuminuric type 1 diabetics than in patients
without complications [41, 45] and microalbuminuric pa-
tients [abstract; Abdel Aziz MY, Nephrol Dial Transplant
12:1538a, 1997]. Other studies reported no differences in
VEGF levels between type 1 diabetic patients with and
without (micro)albuminuria [43, 44, 46]. Correlations be-
tween VEGF levels and glycemic control, severity of dia-
betic nephropathy, and degree of UAE were observed in
some [abstract; Abdel Aziz MY, Nephrol Dial Transplant
12:1538a, 1997] [41] but not in all studies [43, 44, 46, 47].
A positive correlation was found between serum VEGF
levels and nailfold capillary permeability in type 1 diabet-
ics [47]. Urinary VEGF excretion was unchanged in pa-
tients with diabetic nephropathy compared with control
subjects [48]. Renal biopsies from patients with diabetic
nephropathy showed fewer glomerular VEGF mRNA
positive cells than biopsies from controls [18]. Glomeru-
lar VEGF expression was highest in the patients with
mildest sclerotic changes and was particularly strong in
viable glomerular podocytes [20], but reduced or absent
in sclerotic glomeruli [20, 49]. Atrophic tubules were neg-
ative for VEGF mRNA, except for a weak signal in distal
tubules, whereas interstitial cells often had pronounced
VEGF mRNA and protein positivity [20]. In patients
with type 1 diabetes and a minimum diabetes duration
of 10 years, the frequency of the +405 CC genotype,
which is associated with lower VEGF protein produc-
tion in peripheral blood mononuclear cells (PBMC) [9],
was increased compared with control subjects [abstract;
Summers AM, J Am Soc Nephrol 13:248A, 2002]. An in-
crease in the −460 T allele was found in patients with mi-
croalbuminuria or proteinuria compared to patients with
normoalbuminuria [abstract; Summers AM, J Am Soc
Nephrol 13:248A, 2002]. The D allele and DD genotype
of the VEGF D/I polymorphism at −2549 of the promo-
tor region were associated with susceptibility to diabetic
nephropathy in type 1 diabetics and the presence of the
D allele was linked to increased transcriptional activity
[12].
Type 2 diabetes. Renal and/or glomerular VEGF
mRNA were increased in diverse experimental mod-
els of type 2 diabetes [i.e., modestly in insulin-resistant
Zucker fatty/fatty rats and more pronounced in Zucker
diabetic fatty (ZDF) rats [40], in db/db mice [50], and in
Otsuka Long-Evans Tokushima fatty (OLETF) rats] [51].
In OLETF rats, VEGF mRNA expression was increased
only in the early period of diabetic nephropathy [51]. In
ZDF rats, VEGF mRNA levels rose early in the course of
diabetes and remained elevated up to 7 months [52]. At
9 months, when glomerulosclerosis was most pro-
nounced, renal VEGF mRNA levels were reduced [52].
VEGFR-1 and VEGFR-2 mRNA were also elevated in
ZDF rats [40]. Treatment with anti-VEGF-antibodies in
2006 Schrijvers et al: VEGF in renal pathophysiology
db/db mice attenuated the diabetes-associated increases
in kidney weight, glomerular volume and UAE, and
abolished the increase in basement membrane thickness
and creatinine clearance [53]. In addition, the antibodies
tended to reduce the mesangial matrix expansion [53]. In
contrast, in Goto-Kakizaki rats, an experimental model of
lean type 2 diabetes, anti-VEGF-antibodies only tended
to reduce glomerular hypertrophy and had no effect on
UAE or creatinine clearance [abstract; Schrijvers BF,
J Am Soc Nephrol 13:764A, 2002]. Treatment of OLETF
rats with temocapril or CS-866, an angiotensin II type 1
receptor (AT1) antagonist, improved glomerulosclerosis,
reduced urinary protein excretion and VEGF staining,
suggesting that AT1 may be involved in the overproduc-
tion of VEGF in diabetic nephropathy [54].
Plasma VEGF levels were higher in type 2 diabetics
than in controls [55]. In another study, plasma VEGF
levels were elevated only in type 2 diabetic patients
with characteristics of atherosclerosis [56]. Plasma VEGF
tended to rise with increasing UAE [55], however, other
studies reported no such correlation [47, 57]. In type 2 di-
abetic patients, VEGF did not correlate with serum cre-
atinine [57] or capillary permeability [47]. There were
no differences in sVEGFR-1 plasma levels between dia-
betic patients with or without atherosclerosis and con-
trol subjects [56]. Urinary VEGF excretion increased
with the progression of diabetic nephropathy and cor-
related weakly with the levels of serum creatinine, crea-
tinine clearance, microalbuminuria, and proteinuria [16].
In biopsies with mild changes of diabetic nephropathy,
VEGF was up-regulated in glomerular podocytes and
distal tubular cells. In biopsies with advanced changes,
VEGF staining was decreased or negative in sclerotic
glomeruli but remained intense in tubules [16]. More
recently, in patients with type 2 diabetic nephropathy,
glomerular VEGF mRNA expression, observed predom-
inantly in podocytes, was higher than in normal kidneys,
but in contrast to the previous study, VEGF expression
was higher in patients with advanced renal morphologic
changes than in patients with mild-moderate mesangial
expansion and tubulointerstitial changes [abstract;
Kanesaki Y, J Am Soc Nephrol 13:8A, 2002]. In glomeruli
of type 2 diabetic patients, VEGF mRNA level was
inversely related to albumin excretion rate [abstract;
Bortoloso E, Diabetologia 42:273A, 1999]. Tubuloint-
erstitial VEGF and VEGFR-1 mRNA were lower in
patients with severe diabetic nephropathy [58]. While
the ratio between VEGF 121 and VEGF 165 correlated
with mesangial matrix expansion in one study [abstract;
Bortoloso E, Diabetologia 42:273A, 1999], no relation
with the severity of the histologic changes was found
in another [58]. As VEGF 121 is freely diffusable and
VEGF 165 is mostly bound to extracellular matrix, the
pathophysiologic relevance of the ratio between both iso-
forms remains to be determined.
Conclusion. Data regarding circulating VEGF levels
in patients with diabetes are highly discrepant. As VEGF
is a paracrine mediator, systemic levels may not ade-
quately reflect changes in the local VEGF system [43]. In
addition, the assay methods vary substantially between
the studies (i.e., VEGF isoform specificity, detection of
total or free VEGF and interference with VEGF-binding
molecules such as a 2 -macroglobulin) [59]. Finally, deter-
minations of serum and plasma VEGF levels may dif-
fer, owing to release from platelets and leukocytes after
sampling [60, 61]. Renal expression of VEGF and its re-
ceptors is more consistently up-regulated in experimental
animals and patients with type 1 and type 2 diabetes, espe-
cially early in the course of diabetes (Table 1). Inhibition
of VEGF resulted in beneficial effects on the diabetes-
associated renal changes, underlining a deleterious role
for VEGF in the pathophysiology of diabetic nephropa-
thy. Although the cause of the up-regulation of the VEGF
system in diabetes remains unknown, several factors rel-
evant to the pathogenesis of diabetic nephropathy have
been shown to promote VEGF expression in different cell
types, including hyperglycemia, AGEs, PKC, angiotensin
II, various cytokines, and aldose reductase.
High protein–induced nephropathy
One study examined the potential role of VEGF in
high protein–induced renal and glomerular enlargement
(Table 1) [62]. Mice fed a diet containing 45% protein
exhibited early glomerular hypertrophy and kidney
enlargement compared with mice on a 20% protein con-
taining diet. Treatment with a monoclonal neutraliz-
ing VEGF-antibody abolished the high protein–induced
glomerular hypertrophy without affecting kidney or body
weight. Kidney IGF-I was up-regulated in high protein–
fed mice and not affected by treatment with the VEGF-
antibody. Consequently, as IGF-I has been implicated
in high protein–induced renal growth, VEGF could be
a downstream mediator of IGF-I. This study illustrates
that VEGF plays a major role in high protein-induced
glomerular growth [62].
Nephron reduction
Uninephrectomized mice are characterized by an in-
creased glomerular volume and kidney weight in the rem-
nant kidney and an early transient increase in kidney
IGF-I concentration [63]. To explore a role for VEGF
in compensatory renal changes after uninephrectomy,
these animals were treated with anti-VEGF-antibodies,
which abolished the glomerular enlargement and par-
tially blocked the renal growth without affecting re-
nal IGF-I levels [63]. After a 75% surgical nephron
reduction, the remnant kidneys of C57Bl6xDBA2/F1
mice displayed compensatory glomerular and tubular
 Table 1. Summary of the expression and intervention data per disease type in experimental models and patient populations
Effects
Renal expression
Manipulation of GFR/creatine
Disease VEGF VEGFR-1 VEGFR-2 VEGF axis clearance/RF UAE KW/GV Others
Type 1 diabetes Exp ↑ (19,38–40) ↑ (40) ↑ (19,40) VEGF neutralizing ↓ (35) ↓ (35) ↓ (35) ↓ NOS3 (35)
antibodies (35)
Clin ↑ (20) ND ND ND
↓ (18,49)a
Type 2 diabetes Exp ↑ (40,50–52) ↑ (40) ↑ (40) VEGF neutralizing ↓ (53) ↔ (a) ↓ (53) ↔ (a) ↓ (53) ↔ (a) ↓ BMT (53)
antibodies (53, a)
↓ (52)a ACE inhibition, AT1 ↓ (54) ↓ VEGF, GS (54)
antagonism (54)
Clin ↑ (16, b) ↓ (58) ND ND
↓ (16)a
HPN Exp ND ND ND VEGF neutralizing ↔/↓ (62) ↔ Kidney IGF-I (62)
antibodies (62)
Clin ND ND ND ND
Nephron reduction Exp ↑ (64) ND ND VEGF neutralizing ↓ (63) ↔ Kidney IGF-I (63)
antibodies (63)
↓ (65–68) VEGF 121 (66) ↑ EC prolif, ↑ NOS3, ↓ F (66)
ACE inhibition (68) ↑ GFR (68) ↓ (68) ↔ (68) ↑ EC density, ↑ VEGF, ↓ GS (68)
Clin ND ND ND ND
MCN Exp ↓ (85) ↓ (85) ↓ (85) VEGF 165 antagonizing ↔ (36) ↔ Pc ultrastructure,
aptamer (36) ↔ EC fenestration (36)
↑ (86) ↑ (86) ↑ (86)
Clin ↑ (18) ND ND ND
↔ (49,90)
MGN Exp ND ND ND VEGF 165 antagonizing ↔ (36) ↔ Pc ultrastructure (36)
aptamer (36)
Clin ↔ (18,90) ND ND ND
↑ (49)b
↓ (49)a ↓ (94) T
MPGN Exp ↑ (27,101) ND ↑ (27,101) VEGF 165 antagonizing ↓ EC prolif, ↑ GS (36)
aptamer (36)
Schrijvers et al: VEGF in renal pathophysiology

↓ (103) + UNX VEGF 165 (104) ↑ EC prolif (104)

Clin ↑ (90)b ↑ (90) ↑ (90) ND
↓ (27,49,90)a
CGN Exp ↓ (105)a ND ND VEGF 165 (c) ↑ RF (c) ↓ (c) ↑ EC prolif (c)
Clin ↔ (49,88)b ND ND ND
↓ (49,88)a
FSGS Exp ↓ (d) ND ND ND
Clin ↔ (49,90)b ND ND ND
↓ (49,90)a
TMA/HUS Exp ↑ (106) ND ND VEGF 121 (107,108) ↑ RF (107) ↑ Capillary recovery (107),
preservation (108), ↓ F (107)
Clin ↓ (e) T ↑ (e) ↑ (e) ND
Acute rejection Exp ND ND ND ND
Clin ↔ (110) ND ND ND
Chronic rejection Exp ↔ (111) ND ND ND
Clin ↑ (20,110) ND ND ND
↓ (20)a
2007
 2008 Schrijvers et al: VEGF in renal pathophysiology

hypertrophy with prominent cortical peritubular capil-

↑ Damage, BUN, hematuria

Abbreviations used: BMT, basement membrane thickness; CGN, crescentic glomerulonephritis; Clin, clinical; DM, diabetes mellitus; EC, endothelial cell; Exp, experimental; F, fibrosis; FSGS, focal segmental
glomerulosclerosis; GFR, glomerular filtration rate; GS, glomerulosclerosis; GV, glomerular volume; HPN, high protein–induced nephropathy; HUS, hemolytic uremic syndrome; IGF-I, insulin-like growth factor
I; KW, kidney weight; MCN, minimal change nephropathy; MGN, membranous glomerulonephritis; MPGN, mesangioproliferative glomerulonephritis; NOS3, endothelial nitric oxide synthase; Pc, podocyte; prolif,
proliferation; RF, renal function; T, tubuli; TMA, thrombotic microangiopathy; UAE, urinary albumin excretion; UNX, uninephrectomy; ↓ reduced; ↑ enhanced; ↔ no change; ND, no data; (a) abstract; Schrijvers BF,
J Am Soc Nephrol 13:764A, 2002; (b) abstract; Kanesaki Y, J Am Soc Nephrol 13: 8A, 2002; (c) abstract; Shimizu A, J Am Soc Nephrol 13:36A, 2002; (d) abstract; Kairaitis LK, J Am Soc Nephrol 13:336A, 2002; (e)
↓ VEGF, ↓ VEGFR-2, ↓ F (113)
lary growth, whereas another strain, FVB/N mice, addi-
↓ Structural damage (116) tionally developed severe tubulointerstitial lesions and
glomerulosclerosis [64]. While total kidney VEGF pro-
Others

tein levels were increased, VEGF immunostaining re-

vealed a decrease in proximal tubules, a marked increase
in some distal tubules and no change in the glomeruli. In
mice with severe tubulointerstitial injury, the changes
in the peritubular microcirculation and VEGF expres-
(115)

sion were more prominent [64]. In the rat, experimen-

tal nephron reduction resulted in early peritubular and
KW/GV

glomerular endothelial cell proliferation followed by

a progressive loss of peritubular and glomerular cap-
illaries, the latter associated with a decreased VEGF
staining in tubules and glomerular podocytes [65–68].
↓ (115)
UAE

In another study, VEGF mRNA and protein expression

Effects

was increased 2 weeks, but decreased 4 weeks after 5/6

nephrectomy [abstract; Horike H, J Am Soc Nephrol
13:164A, 2002]. Administration of VEGF 121 after ex-
GFR/creatine
clearance/RF

perimental nephron reduction increased glomerular and

peritubular endothelial cell proliferation and reduced
tubulointerstitial fibrosis [66]. In addition, VEGF 121 in-
creased renal NOS3 staining and 24-hour urinary nitrite
and nitrate excretion [66], which is consistent with the
observation that VEGF-induced angiogenesis is me-
Table 1. (Continued)

ACE inhibition, AT1

Manipulation of

antagonism (113)
VEGF neutralizing
antibodies (115)

diated by nitric oxide. NOS blockade with L-N(G)-

VEGF axis

VEGF 121 (116)

nitro-arginine-methyl-ester (L-NAME) in animals with

remnant kidneys accelerated the development of pro-
teinuria, glomerulosclerosis, and tubulointerstial fi-
brosis, along with more glomerular and peritubular
ND
ND
ND
ND
ND
ND
ND
ND
ND

endothelial cell loss and impaired endothelial pro-

liferation [67]. VEGF immunostaining in glomerular
Sclerotic glomeruli or crescents in crescentic glomerulonephritis; b Preserved glomeruli.
↑ (112–114)
VEGFR-2

podocytes and tubules was not different between the

↔ (121)
↑ (118)
↑ (120)

groups [67]. In rats with subtotal nephrectomy, treat-

ment with perindopril improved glomerular filtration rate
ND
ND

ND
ND

ND
ND

and endothelial cell density, reduced UAE and glomeru-

Renal expression

losclerosis and restored VEGF expression [68]. Taken

↑ (112–114)
VEGFR-1

together, the experimental studies (Table 1) suggest that

↔ (120)
↑ (118)

VEGF is required for the glomerular and tubular hyper-

ND
ND

ND
ND
ND
ND
ND

trophy and endothelial cell proliferation in response to

nephron reduction. Down-regulation of VEGF may re-
abstract; te Loo DM, J Am Soc Nephrol 13:251A, 2002.

sult in the development of glomerulosclerosis and tubu-

↑ (112–114)
VEGF

lointerstitial fibrosis.
↔ (119)

↔ (121)
↑ (117)
↑ (118)

↑ (123)
↓ (49)

Human data regarding uremia and VEGF expression

ND

ND
ND

ND

are rather scarce. VEGF plasma levels were higher in

uremic patients than in control subjects [55, 69]. The rea-
Clin

Clin

Clin

Clin

Clin
Exp

Exp

Exp

Exp

Exp

sons for higher VEGF levels in uremia are unknown, but

excess production, tissue hypoxia, or reduced clearance
of VEGF have been suggested [55, 68]. The negative
Ischemia/reperfusion

correlation between plasma VEGF levels and residual

nephrotoxicity

Lupus nephritis

renal function observed in peritoneal dialysis patients

Congenital NS
Cystic kidney
Cyclosporine

suggests that renal clearance contributes to the elimina-

diseases

tion of VEGF. Conversely, VEGF may have a negative

injury
Disease

impact on residual renal function [70].

a
 Schrijvers et al: VEGF in renal pathophysiology
Glomerulonephritis
Minimal change nephropathy. Minimal change
nephropathy (MCN) has been speculated to result from
the release of soluble circulating factors by mononuclear
cells that alter glomerular permeability. As VEGF may
be a regulator of glomerular permeability, the release of
VEGF by PBMC has been scrutinized. In cultured PBMC
from patients with MCN, the effects of various cytokines
on the secretion of VPF in the culture supernatant were
investigated [71–80]. VPF is an older term for VEGF
and is determined by quantifying the intradermal per-
meability in guinea pigs. Cultured PBMC, activated by
concanavalin-A or lipopolysaccharide, secreted VPF [71–
82] and the VPF levels in the culture supernatant were
higher in PBMC from nephrotic MCN patients than from
patients in remission or control subjects [71–80]. IL-2,
IL-12, IL-15, and IL-18 stimulated and TGF-b1, IL-4, IL-
10, and IL-13 inhibited VPF release by activated PBMC
from patients with MCN [71–79]. Patients treated with
steroids had lower VPF levels in PBMC supernatant than
untreated patients [71–78]. In contrast, VEGF mRNA
expression in unstimulated PBMC was not different be-
tween children with steroid-sensitive nephrotic syndrome
(SSNS) in relapse and children with SSNS in remis-
sion [83] or controls [84]. The potential role of VEGF
in the development of proteinuria was also investigated
in experimental MCN [85, 86]. In puromycin aminonu-
cleoside nephrosis (PAN) rats, an experimental model
of human MCN, the renal mRNA expression of VEGF
and its receptors VEGFR-2 and VEGFR-1 was down-
regulated [85]. In contrast, in hyperalbuminemia-induced
rat nephrosis, another model of human MCN, VEGF and
its receptors were up-regulated and correlated with the
severity of proteinuria [86]. In PAN rats, treatment with
a VEGF 165 aptamer for 6 days did not affect proteinuria,
podocyte swelling, foot-process fusion, or glomerular en-
dothelial fenestrations [36], suggesting that VEGF 165 is
not involved in the disease process, although a pathogenic
role for other isoforms is not excluded. Plasma VEGF
concentrations (free VEGF 121 and VEGF 165 ) and
urine VEGF/creatinine ratios were not elevated during
relapses of childhood SSNS when compared with remis-
sion and normal controls [84]. Likewise, plasma or uri-
nary VEGF levels were not different between patients
with MCN in the nephrotic state and those in remis-
sion [83] or healthy controls [87, 88]. In contrast, urinary
VEGF levels were increased in patients with MCN with
nephrotic syndrome when compared with patients with-
out nephrotic syndrome and healthy controls, and corre-
lated with the degree of proteinuria [89]. Urinary VEGF
levels decreased rapidly after steroid therapy [89]. Pa-
tients with MCN in the nephrotic state and in remission
displayed a similar VEGF protein and mRNA expres-
sion mainly localized in glomerular podocytes [90]. In
contrast, in situ hybridization revealed that VEGF
2009
mRNA expression was up-regulated in podocytes in
MCN and correlated with the urinary protein excretion
[18]. In two patients with systemic lupus erythematosus
(SLE) and minimal light microscopic changes VEGF ex-
pression was normal [49]. The allele frequencies of the
dinucleotide repeat polymorphisms within the VEGFR-
1 gene were not different between patients with MCN
and normal controls [91]. Similarly, polymorphisms in the
VEGF gene promotor were not associated with the de-
velopment of proteinuria in MCN [abstract; Watson CJ,
J Am Soc Nephrol 9:A2497, 1998]. Further, the genotype
frequencies of the VEGF gene polymorphisms −460 C/T,
−141 A/C, and +405 G/C were not different in children
with SSNS versus controls [92].
The lack of consistent alterations in the VEGF system
in experimental animals or patients with MCN (Table 1),
does not allow firm conclusions to be drawn about the
role of VEGF in the pathophysiology of MCN. Method-
ologic difficulties may interfere with the correct interpre-
tation of the results. PBMC in culture may be in anaerobic
metabolism, which may affect the expression of VEGF.
Pitfalls in the determination of circulating VEGF lev-
els have been described above. Further, high urinary
VEGF levels may merely reflect podocyte loss and uri-
nary podocyte excretion [93] rather than an active in-
volvement of VEGF in the disease process. It has even
been suggested that urinary VEGF may be derived from
the circulation and as such may be nothing more than an
assay for proteinuria [89].
Membranous glomerulonephritis. Cultured lympho-
cytes from nephrotic membranous glomerulonephritis
(MGN) subjects did not release VPF in their super-
natants [82]. In rats with passive Heymann nephritis, an
experimental model of MGN, proteinuria, podocyte foot-
process fusion and subepithelial immune deposits were
not affected by treatment with a VEGF 165 aptamer for
7 days [36]. Urinary VEGF excretion was decreased in
patients with idiopathic MGN compared with control
subjects, but did not correlate with serum VEGF, renal
function or proteinuria [48]. In the follow-up of some pa-
tients, however, a reduction of proteinuria was associated
with increasing urinary VEGF excretion and the change
in proteinuria over one year correlated inversely with the
change in urinary VEGF [48]. As mentioned above, de-
creased VEGF excretion in MGN may be explained by
podocyte injury and increased VEGF excretion during
clinical improvement by partial recovery of podocytes.
In 10 nephrotic MGN patients with already a significant
degree of glomerulosclerosis, there was no difference in
renal VEGF mRNA expression compared with normal
kidneys and no correlation between VEGF expression
and the degree of proteinuria [18]. Another study, in-
cluding two patients with membranous nephropathy, one
idiopathic and one lupus nephritis class IV, reported kid-
ney VEGF protein and mRNA expression to be similar
2010 Schrijvers et al: VEGF in renal pathophysiology
as in controls and localized mainly in podocytes [90]. In
three other cases of MGN, VEGF mRNA and protein ex-
pression was strong in relatively preserved glomeruli but
decreased or absent in sclerotic areas [49]. A recent study
demonstrated reduction of VEGF immunostaining in the
tubular epithelium of MGN patients versus controls [94].
The C allele of the VEGF −460 C/T polymorphism was
associated with progression toward end-stage renal fail-
ure in patients with idiopathic membranous nephropa-
thy [abstract; Summers AM, J Am Soc Nephrol 13:260A,
2002].
No consistent pattern of changes in the VEGF system
emerges from these studies (Table 1). Difficulties with
the interpretation of urinary VEGF levels have been de-
scribed above. The discrepant results of VEGF expres-
sion in renal biopsies of patients with MGN are likely
due to differences in the degree of glomerulosclerosis, as
loss of podocytes implicates loss of VEGF. It thus remains
unclear whether VEGF plays a role in the pathophysiol-
ogy of MGN.
Membranoproliferative glomerulonephritis. The
POEMS syndrome is a multisystemic syndrome charac-
terized by polyneuropathy, organomegaly, endocrinopa-
thy, M protein, and skin changes. Renal involvement can
occur and has been described as membranoproliferative
glomerulonephritis-like lesions [95]. Circulating VEGF
levels were elevated in POEMS syndrome compared
with normal controls [96, 97] or with patients with pri-
mary membranoproliferative glomerulonephritis [98].
There was no difference in serum VEGF levels between
POEMS patients with and without renal involvement
[98]. Further, serum VEGF levels in POEMS patients
did not correlate with glomerular alterations [95].
Mesangioproliferative glomerulonephritis (MPGN).
PBMC of patients with IgA nephropathy (IgAN) re-
sponded similarly to cytokines as those of MCN pa-
tients, with stimulation of VPF release by IL-2, IL-12,
IL-15, and IL-18 and inhibition by TGF-b1, IL-4, IL-
10, and IL-13 [71–78]. In contrast, VEGF mRNA lev-
els in unstimulated PBMC were not different between
IgAN patients and healthy volunteers and did not
correlate with clinical or pathologic parameters [99].
Incubation of human mesangial cells with aberrantly gly-
cosylated IgA resulted in a down-regulation of VEGF
mRNA expression and decreased VEGF release in
the culture medium [100]. During recovery of anti-
Thy 1.1 nephritis, an experimental model of MPGN,
up-regulation of VEGF mRNA in podocytes and the
mesangial region, and of VEGFR-2 mRNA in the
glomerular capillary walls was associated with endothe-
lial cell proliferation (Table 1) [27, 101]. In accordance,
administration of a VEGF 165 antagonizing aptamer re-
duced glomerular endothelial cell proliferation and inhib-
ited glomerular capillary repair resulting in glomerular
sclerosis [36]. Glucocortocoids decreased VEGF release
and aggravated proteinuria in anti-Thy 1.1 nephritic rats
possibly due to impairment of glomerular endothelial
repair [102, 103]. Rats with anti-Thy 1.1 nephritis com-
bined with uninephrectomy [103] or Habu-snake venom
injection [104] developed progressive glomerulosclerosis
and renal insufficiency. In the former model, regenera-
tion of glomerular endothelial cells and VEGF mRNA
expression were decreased [103]. In the latter model,
the administration of recombinant human VEGF 165 en-
hanced endothelial cell proliferation and glomerular
capillary repair [104]. Serum VEGF levels were not dif-
ferent in patients with IgAN compared with normal con-
trols [87, 88]. In contrast, urinary VEGF levels were
increased in patients with IgAN with nephrotic syndrome
when compared with patients without nephrotic syn-
drome and healthy controls, and correlated with the de-
gree of proteinuria [89]. In patients with MPGN due to
IgAN, Henoch-Schönlein nephritis, non-IgA prolifera-
tive glomerulonephritis and lupus nephritis, VEGF pro-
tein and mRNA were expressed by glomerular podocytes
and mesangial cells but were faint or absent in areas of
glomerulosclerosis (Table 1) [49, 90]. In patients with
early primary MPGN [90] or IgAN, expression of VEGF
and its receptors was up-regulated, but in IgAN patients
with more severe interstitial damage, VEGF staining
was decreased [abstract; Horike H, J Am Soc Nephrol
13:164A, 2002] [27]. In patients with MPGN, including
IgAN, the presence of the VEGF −460 CC genotype or
C allele was associated with progression toward end-stage
renal disease [abstract; Summers AM, J Am Soc Nephrol
13:260A, 2002].
In conclusion, VEGF may be essential for glomerular
repair in MPGN. Depressed VEGF synthesis resulting
from podocyte injury may contribute to endothelial cell
loss and favor the development of glomerulosclerosis.
Crescentic glomerulonephritis. In mice with anti-
glomerular basement membrane glomerulonephritis, an
experimental model of crescentic glomerulonephritis,
loss of glomerular capillaries was temporally associated
with decreased VEGF, VEGFR-2, Ang-1, and Tie2 im-
munostaining and up-regulation of Ang-2, especially in
glomeruli with crescents or sclerosis (Table 1) [105]. In
antiglomerular basement membrane glomerulonephritis
rats, treatment with VEGF 165 resulted in recovery of the
necrotizing and crescentic lesions, proliferation of en-
dothelial cells and capillary repair, and improved renal
function and proteinuria [abstract; Shimizu A, J Am Soc
Nephrol 13:36A, 2002]. Serum VEGF levels were higher
in patients with crescentic glomerulonephritis, includ-
ing pauci-immune rapidly progressive glomerulonephri-
tis, Henoch-Schönlein purpura nephritis and IgAN, than
in normal control subjects or in patients with MCN, IgAN,
and focal segmental glomerular sclerosis (FSGS) [49, 87,
88]. Serum VEGF levels correlated with crescent fre-
quency, tubulointerstitial injury, and glomerular mono-
cyte infiltration, but not with urinary protein excretion or
serum creatinine levels [49, 87, 88]. Serum VEGF levels
 Schrijvers et al: VEGF in renal pathophysiology
decreased after corticosteroid therapy [49, 88]. VEGF ex-
pression was normal in glomeruli with preserved architec-
ture but decreased or absent in glomeruli compressed by
crescents and in sclerotic areas (Table 1) [49, 88]. Taken
together, the experimental data suggest that VEGF
accelerates glomerular recovery in crescentic glomeru-
lonephritis. Further, for the first time, a role for angiopoi-
etins in glomerular disease is suggested. Up-regulation of
Ang-2 may be an appropriate adaptive response to pro-
mote new vessel formation, but in the presence of low
VEGF levels it may contribute to endothelial apoptosis
and vessel regression [14].
FSGS. VEGF mRNA expression in unstimulated
PBMC was higher in children with FSGS than in those
with MCN but the difference was not significant [83].
Rats developed proteinuria after the injection of the su-
pernatant of cultured PBMC from FSGS patients sug-
gesting that a “glomerular permeability factor” released
from PBMC may change glomerular permeability and
result in proteinuria in FSGS [81]. In a murine FSGS
model, adriamycin nephrosis, areas of interstitial expan-
sion and tubular atrophy were associated with increased
staining of hypoxia inducable factor-1 (HIF-1) in tubular
and interstitial cells, reduced VEGF staining and loss of
cortical microvasculature [abstract; Kairaitis LK, J Am
Soc Nephrol 13:336A, 2002). Plasma VEGF levels were
higher in proteinuric patients with FSGS than in those
with MCNS but the difference was not significant [83].
Serum VEGF levels in FSGS patients were not different
from those in control subjects [48, 87, 88]. Urinary VEGF
excretion, on the other hand, was higher than normal
in patients with FSGS, but did not correlate with serum
VEGF, renal function, or proteinuria [48]. In patients
with FSGS, VEGF protein and mRNA expression were
normal in preserved glomeruli but absent or very low
in glomeruli with segmental or global sclerosis (Table 1)
[49, 90]. Rare polymorphisms in the VEGF gene promo-
tor were not associated with the development of protein-
uria in FSGS [abstract; Watson CJ, J Am Soc Nephrol
9:A2497, 1998]. In contrast, the CC genotype and C al-
lele of the more common −460 C/T polymorphism were
associated with progression to end-stage renal disease in
patients with FSGS [abstract; Summers AM, J Am Soc
Nephrol 13:260A, 2002].
The low renal VEGF expression and increased urinary
VEGF excretion in FSGS may be secondary to podocyte
injury and loss in the urine. No solid conclusions on the
role of VEGF in the pathophysiology of FSGS can thus
be drawn.
Thrombotic microangiopathy (TMA)/hemolytic
uremic syndrome (HUS)
A rat model of renal TMA with histologic features
similar to human HUS was induced by antiglomerular
endothelial cell antibodies which produced loss of
2011
glomerular and peritubular capillary endothelium [106].
An early transient increase in VEGF immunostain-
ing was observed in glomerular podocytes and corti-
cal tubules, but despite proliferation of glomerular and
peritubular endothelial cells, progressive glomerular and
tubulointerstitial damage, and renal failure developed
[106]. The hypothesis that angiogenic growth factors may
accelerate recovery of renal microvascular injury was
studied in experimental TMA (Table 1) [107, 108]. Sub-
cutanous administration of VEGF 121 resulted in greater
recovery of the renal microvasculature together with a
better renal function and less tubulointerstitial fibrosis
[107]. VEGF 121 -treated rats had higher urinary nitrites
and nitrates excretion, suggesting that the angiogenic ef-
fects of VEGF were mediated by nitric oxide [107]. In
a more severe form of renal TMA in rats with acute
massive renal infarction, VEGF administration resulted
in reduced glomerular endothelial cell apoptosis, pre-
served microvascular endothelium and less cortical and
medullary necrosis [108]. Elevated serum and plasma
VEGF levels were found in HUS patients compared with
controls and correlated with the severity of the disease
[abstract; te Loo DM, J Am Soc Nephrol 13:251A, 2002].
In three patients with HUS, immunohistochemistry of
renal biopsy material showed increased VEGFR-1 and
VEGFR-2 in the glomeruli, and absent VEGF staining
in tubuli compared to controls [abstract; te Loo DM, J Am
Soc Nephrol 13:251A, 2002). In conclusion, VEGF may
be required for glomerular and tubulointerstitial repair
in TMA.
Renal transplantation
Acute rejection. To study the possible relationships
between VEGF gene polymorphisms and the risk of
acute renal allograft rejection, single nucleotide substi-
tutions in the VEGF gene were identified in 173 white
renal allograft recipients [109]. The correlation between
VEGF gene polymorphisms and VEGF production was
investigated in vitro in PBMC from healthy individuals.
Homozygotes with −1154G/G genotype and −2578C/C
genotype showed the greatest risk of rejection and had
the highest production of VEGF by stimulated PBMC
from healthy volunteers, as compared with −1154A/A
and −2578A/A genotypes, respectively. Heterozygotes
with −1154G/A and −2578C/A genotypes demonstrated
an intermediate risk. In biopsies of patients with acute
rejection or temporary allograft dysfunction, VEGF im-
munostaining appeared to be quite similar to that of nor-
mal human kidney, but biopsies from normal kidneys
were not included in this study (Table 1) [110].
Chronic rejection. In the Fischer (F344) donor to
Lewis recipient rat renal allograft, a well-established ex-
perimental model of chronic allograft rejection, no dif-
ferences in VEGF mRNA expression were observed
between allografts and isografts at any time. VEGF
2012 Schrijvers et al: VEGF in renal pathophysiology
expression did not correlate with the extent of
macrophage or myofibroblast infiltration [111]. In kid-
neys from four patients with chronic vascular rejection,
VEGF mRNA and protein expression was increased
compared with normal kidneys, most notably in prox-
imal and distal tubular cells and interstitial cells and
to a lesser extent in vascular smooth muscle cells and
the mononuclear inflammatory infiltrate [20]. Viable
glomerular podocytes displayed marked VEGF mRNA
expression, but VEGF mRNA labeling was reduced
or absent in sclerosed glomeruli [20]. Similarly, in-
creased renal VEGF protein expression was observed
in glomerular podocytes and mesangial cells, vascu-
lar smooth muscle cells, and some endothelial cells
and tubulointerstitium of kidneys in 17 patients with
chronic renal allograft rejection, particularly in intersti-
tial cells likely to be macrophages [110]. Renal VEGF
immunostaining was increased in patients with chronic
rejection when compared with patients with acute re-
jection or temporary allograft dysfunction [110]. The in-
creased VEGF expression in glomeruli and particularly
interstitium of human kidneys with chronic allograft re-
jection may be induced by hypoxia, as a consequence
of reduced blood flow [20]. Other hypotheses for the
up-regulation of VEGF include production of VEGF by
macrophages or proliferating glomerular mesangial cells
[110]. Alternatively, VEGF may contribute to the recruit-
ment of macrophages into the interstitium.
Cyclosporine nephrotoxicity. In a rat model of chronic
cyclosporine nephrotoxicity, VEGF mRNA and protein
expression as well as VEGFR-1 and VEGFR-2 mRNA
expression were up-regulated as early as 7 days after ex-
posure (Table 1) [112–114]. The increased VEGF and
VEGFR-1 expression continued until day 28, whereas
VEGFR-2 expression declined but remained higher than
in control rats [112, 113]. Immunostaining for VEGF was
particularly strong in proximal and distal tubular cells and
occasionally in glomerular podocytes [113]. Treatment
with enalapril or losartan improved the tubulointerstitial
fibrosis and afferent arteriolopathy, and decreased VEGF
mRNA and protein expression and VEGFR-2 mRNA ex-
pression [113]. L-NAME worsened both glomerular fil-
tration rate and cyclosporine-induced interstitial fibrosis
and arteriolopathy, and further increased VEGF mRNA
and protein expression while L-arginine had the oppo-
site effect, suggesting that nitric oxide down-regulates
VEGF expression in cyclosporine nephrotoxicity [114].
In a mouse model of acute cyclosporine toxicity, spe-
cific blockade of VEGF by a monoclonal antibody in-
creased the deleterious effects of cyclosporine on the kid-
ney [115]. Mice treated with the VEGF-antibody showed
enhanced tubular toxicity, more apoptotic nuclei, in-
creased blood urea nitrogen and hematuria compared
with mice treated with cyclosporine alone or with cy-
closporine and an irrelevant IgG [115]. However, urinary
protein excretion was higher in cyclosporine-treated mice
than in cyclosporine and VEGF-antibody–treated mice
[115]. In vitro, the cyclosporine-induced toxicity in cul-
tured murine proximal tubular epithelial cells also in-
creased in the presence of a VEGF antibody [115]. In
a rat model of chronic cyclosporine nephrotoxicity, ad-
ministration of exogenous VEGF 121 resulted in renopro-
tective effects (i.e., osteopontin expression, macrophage
infiltration, collagen III deposition were decreased versus
control rats and afferent arteriolopathy was dramatically
improved) [116]. Treatment with VEGF 121 also lowered
blood pressure, which was suggested to be mediated by
the accelerated recovery from tubulointerstitial and mi-
crovascular injury in VEGF-treated rats [116]. The role
of VEGF in human cyclosporine nephrotoxocity has not
been evaluated.
In summary, the expression of the VEGF system is
increased in experimental cyclosporine nephrotoxicity.
VEGF-blockade aggravated and VEGF-administration
ameliorated the cyclosporine-induced injury, suggesting
a role for VEGF in the repair process induced by cy-
closporine nephrotoxicity.
Other kidney diseases
Cystic kidney diseases. One experimental study inves-
tigated the expressions of VEGF, HIF-1a and HIF-3a
in polycystic kidney lesions that occurred spontaneously
in two rats [117]. Compared with the kidneys of control
rats, VEGF protein expression was increased in the inner
stripe of the outer medulla where cystic alterations were
prominent. HIF-1a and HIF-3a protein expressions were
increased in proximal tubuli and in the thin loop of Henle,
respectively. In kidneys from 14 patients with autosomal-
dominant polycystic kidney disease (ADPKD), increased
angiogenesis was identified, especially in the cyst walls
and around the cysts [118]. In addition, VEGF protein
was expressed in the epithelial cysts cells, VEGFR-2 pro-
tein in some capillaries surrounding the cysts and some
glomeruli, whereas VEGFR-1 was expressed irregularly
in some cyst cells and remnant tubular cells. Furthermore,
VEGF 165 was demonstrated in cultured ADPKD cells
and in their supernatant, and VEGF secretion was in-
creased during hypoxia [118]. In patients with acquired
cystic kidney disease, IL-6, IL-8, and VEGF concentra-
tions were higher in the cyst fluid than in the blood, and
higher than in patients with other cystic nephropathies
(i.e., ADPKD or renal cell carcinoma). Taken together,
these findings suggest an angiogenic role for VEGF in the
pathogenesis of cystic kidney diseases, likely triggered by
local hypoxia [117] and involving the development of a
pericystic circulation which may be necessary for cyst cells
to grow [118].
Ischemia/reperfusion injury. Cultured rat kidney
tubular epithelial cells subjected to hypoxia showed
 Schrijvers et al: VEGF in renal pathophysiology
increased VEGF staining in the periphery of the cells
[119]. In a rat model of renal ischemia/reperfusion injury,
whole kidney VEGF mRNA and protein expression was
not increased following ischemia or ischemia and reper-
fusion, although preexisting VEGF in tubular epithelial
cells redistributed from the cytoplasm to the basolateral
surface [119]. Further, VEGFR-1 mRNA expression was
not changed, whereas VEGFR-2 mRNA expression was
up-regulated most prominent in glomerular endothelial
cells and peritubular capillaries, but also in some tubu-
lar epithelial cells [120]. It was speculated that the in-
creased VEGFR-2 expression in peritubular capillaries
during ischemia/reperfusion injury may direct the effects
of VEGF released by ischemic tubular epithelial cells to
adjacent endothelial cells in order to preserve the cap-
illary blood supply and to promote tubular cell survival
and recovery [120].
Congenital nephrotic syndrome of the Finnish type. In
kidney samples of infants with congenital nephrotic syn-
drome of the Finnish type, expression and localization of
VEGF and VEGFR-2 mRNA was similar to normal adult
human kidney [121]. VEGF protein expression was also
not different from normal kidneys except for an intense
juxtaglomerular staining [121].
Lupus nephritis. VEGF mRNA in PBMC of patients
with SLE did not differ from those of controls [122].
VEGF plasma levels were higher in SLE patients than in
controls, and SLE patients with renal failure had higher
levels than those with normal renal function [123]. VEGF
protein expression was increased in distal tubules, col-
lecting ducts and some podocytes in SLE patients with
moderate renal failure [123]. In two cases of SLE with
diffuse endocapillary proliferative glomerulonephritis,
renal VEGF expression was reduced [49].
Wegener’s granulomatosis. Serum VEGF levels were
higher in patients with Wegener’s granulomatosis than
in normal controls [124]. Serum VEGF levels were
markedly elevated in patients with major disease versus
minor disease activity, suggesting that VEGF may be a
marker of disease activity [124].
Renal cell carcinoma. VEGF promotes the growth
of renal cell carcinoma, by virtue of its angiogenesis-
inducing potential [125]. A detailed description of the
role of VEGF in renal cell carcinoma is, however, beyond
the scope and space limitations of this review.
INTERFERENCE WITH THE VEGF AXIS
Several strategies exist to target VEGF and its re-
ceptors, including VEGF neutralizing antibodies, VEGF
antagonizing aptamers, VEGF receptor-blocking anti-
bodies, VEGF receptor antagonists, and angiopoietins
[126]. So far, the experience with these treatments in
renal disease is limited to animal models. A human-
ized anti-VEGF monoclonal antibody (bevacizumab)
2013
and an anti-VEGF pegylated aptamer (EYE001) are cur-
rently evaluated in clinical trials to treat various types
of cancer, as well as macular degeneration and dia-
betic retinopathy [127, 128]. VEGF receptor antagonists
are also available. SU5416 and ZM323881 are specific
for VEGFR-2, whereas PTK787/ZK222584 inhibits both
VEGFR-1 and VEGFR-2 [126]. Other strategies to re-
duce VEGF-mediated effects, including placenta growth
factor inhibition and drugs that interfere with signaling
molecules in the VEGF signal transduction pathway such
as Src/Fyn kinase inhibitors, are in development or in
early stages of testing [126]. Targeting specific VEGF sig-
naling molecules might be a way to distinctively inhibit
specific actions of VEGF.
Interference with the renin-angiotensin system may be
an indirect means to affect the VEGF axis, but the in-
teraction between both systems is complex. In cultured
mesangial cells angiotensin II induced VEGF expression
[129], whereas in tubular epithelial cells angiotensin II
diminished VEGF expression [65]. In agreement, diver-
gent effects have been reported with in vivo blockade
of the renin-angiotensin system. Angiotensin-converting
enzyme (ACE) inhibition or AT1 antagonism reduced
VEGF expression in diabetic nephropathy [54] and in
cyclosporine nephrotoxicity [113], suggesting that AT1
may be involved in the VEGF overexpression observed
in these pathologies. In contrast, ACE inhibition was as-
sociated with an increased VEGF expression in the rem-
nant kidney [68].
CONCLUSION
The strategic localization of VEGF in the vicinity of the
filtration barrier and its known effects on microvascular
permeability have engendered the hypothesis that VEGF
controls glomerular permeability in the normal adult kid-
ney and induces proteinuria in pathologic conditions. Al-
though a large number of studies have been designed to
examine this hypothesis, none has been able to firmly
support it. Correlations of plasma or urinary VEGF lev-
els with proteinuria in diverse glomerular pathologies
have been inconsistent. Positive correlations between uri-
nary VEGF levels and proteinuria may relate to urinary
podocyte loss rather than to a causative link between
renal up-regulation of VEGF and development of
proteinuria. The inhibition of VEGF in experimental
glomerulonephritis did not affect proteinuria. The laud-
able effect of VEGF-blockade on proteinuria in experi-
mental diabetes may be indirect through inhibition of the
disease process. Finally, podocyte-specific overexpression
of VEGF caused a collapsing glomerulopathy rather than
proteinuria.
The paramount task of VEGF in the adult glomerulus
appears to be the stimulation of capillary endothelial cell
growth and proliferation. This may be inappropriate in
2014 Schrijvers et al: VEGF in renal pathophysiology
diabetic nephropathy where it contributes to glomerular
hypertrophy and hyperfiltration, but may be an essential
repair mechanism in glomerulonephritis and TMA. Sim-
ilarly, tubular cells may respond to hypoxia or injury with
the production of VEGF that stimulates proliferation of
peritubular capillaries in order to overcome the tubular
damage.
As the VEGF system is affected in a wide variety of kid-
ney diseases, interventions to manipulate VEGF may be
promising therapeutic tools. Several strategies to either
inhibit or enhance the VEGF axis have shown promising
results in animal models of renal disease, but no data in
humans are presently available.
The VEGF gene is highly polymorphic and certain
polymorphisms may be associated with alterations in
the expression of VEGF. Although the diagnostic im-
portance of genotyping renal patients remains to be
established, some VEGF polymorphisms may develop
into useful markers of disease susceptibility and/or
progression.
ACKNOWLEDGMENTS
B. Schrijvers is supported by the Institute for the Promotion of
Innovation by Science and Technology in Flanders (IWT), A. Flyvb-
jerg is supported by the Danish Diabetes Association, the Eva and
Henry Frænkels Memorial Foundation, and the Danish Medical Re-
search Council.
Reprint requests to An De Vriese, Renal Unit, AZ Sint-Jan AV Rud-
dershove 10, B-8000 Brugge, Belgium.
E-mail: an.devriese@UGent.be
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