Protein kinase C and the vascular complications of diabetes mellitus

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Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Protein kinase C and the vascular complications of diabetes mellitus

Author
Eli A Friedman, MD

Section Editors
Richard J Glassock, MD, MACP
David M Nathan, MD

Deputy Editor
John P Forman, MD, MSc

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2015. | This topic last updated: May 06, 2015.
INTRODUCTION Among patients who have had diabetes mellitus for five or more years, vascular
dysfunction results in nephropathy, retinopathy and at least some forms of neuropathy. The most likely cause of
vascular dysfunction is chronic hyperglycemia, although hyperglycemia alone may not be sufficient to cause
microvascular disease [1,2]. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and
"Glycemic control and vascular complications in type 2 diabetes mellitus".)
Numerous mechanisms have been proposed to explain the association between hyperglycemia and vascular
complications (algorithm 1) [3,4]. These include:
Increased activation of the polyol (or aldose reductase) pathway. Increased aldose reductase activity
results in the depletion of NADPH, a decrease in cellular reduced glutathione levels, and increased
oxidative stress [4].
Increased activity of the hexosamine pathway, which may alter gene expression and protein function [4].
Increased formation of advanced glycated end products (AGEs) [5], which may activate protein kinase C
(PKC) isoforms [6]. The mechanisms of oxidant-induced interaction between PKC isoforms and AGEs
resulting in vascular disease are incompletely defined [7].
Hemodynamic alterations (increased capillary pressures and flows).
Tissue hypoxia and oxidative stress.
Increased activity of vascular PKC isoform(s) [8].
This topic reviews the role of PKC in the pathogenesis of diabetic complications. The pathogenesis of diabetes
mellitus and the roles of specific proteins in insulin regulation and resistance are discussed elsewhere. (See
"Pathogenesis of type 1 diabetes mellitus" and "Pathogenesis of type 2 diabetes mellitus" and "Classification of
diabetes mellitus and genetic diabetic syndromes", section on 'Genetic defects'.)
STRUCTURE AND FUNCTION The reversible phosphorylation of proteins is a common means of governing
protein activity within cells. Phosphates are transferred from ATP molecules onto target molecules by protein
kinases and are removed by protein phosphatases (figure 1). In most, but not all, circumstances, the activated
kinase "turns on" the next target by the addition of the phosphate and is "turned off" with the removal of the
phosphate by a protein phosphatase. Within each cell, a large variety of kinases and phosphatases play a
central role in intracellular signaling.
Protein kinases belong to a large family of enzymes that contain a similar 250 amino acid catalytic (kinase)
domain that is responsible for the phosphate transfer to the target protein. They differ according to the amino
acids on either side of the kinase domain. These variable amino acids provide specificity and permit the
recognition and phosphorylation of unique sets of proteins by each protein kinase. Other amino acid sequences
within the kinase domain permit enzyme activity to be regulated (on or off) in response to specific signals.
Kinases recognize target phosphorylation sites by the surrounding amino acid sequences, which are common
to many proteins.

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ROLE OF PKC IN VASCULAR COMPLICATIONS Protein kinase C (PKC) activity is increased in both
experimental animals [9,10] and humans [11-13] with diabetes. The hyperglycemia-induced increase in PKC
activity is most likely mediated by enhanced de novo synthesis of diacylglycerol (DAG), which is a major
endogenous activator of PKC [14]. Diacylglycerol (DAG) levels are chronically elevated in the setting of
hyperglycemia because of the increased availability of the DAG precursor, glycerol 3-phosphate [3]. Reactive
oxygen species, free fatty acids, and growth factors may also contribute to PKC activation in diabetic patients
[15]. Multiple PKC isoforms appear to be activated by hyperglycemia [3].
The activation of PKC initiates a complex network of intracellular signaling that may alter transcription factor
binding to the promoter regions of responsive genes, which alters gene expression [16]. Increases in vascular
permeability, angiogenesis, cell growth and apoptosis, vessel dilation, cytokine activation, basement membrane
thickening and extracellular matrix expansion have all been observed with increased PKC activity [3,17].
Sustained alterations in PKC-regulated gene expression in vascular cells may contribute to some of the
characteristic vascular abnormalities in diabetes mellitus.
Diabetic nephropathy Experiments in diabetic mice and rats support a role for PKC in the pathogenesis of
diabetic nephropathy:
PKC activity is increased in glomeruli isolated from diabetic rats [18] and in mesangial cells cultured in
high glucose [10].
PKC inhibition prevents the glycated albumin-induced or glucose-induced increase in basement
membrane type IV collagen production by glomerular endothelial [19] and mesangial [20] cells.
PKC increases levels of mRNA that encode matrix components in glomeruli isolated from streptozotocin
(STZ)-induced diabetic rats [21].
PKCdelta promotes tubular cell injury and death in kidneys of STZ-induced diabetic mice [22].
PKC activation has been associated with alterations in renal and glomerular blood flow, basement
membrane thickening, extracellular matrix expansion, increased vascular permeability, enhanced
angiogenesis, excessive apoptosis, and alterations in enzyme activation of Na(+)-K(+)-ATPase, cPLA(2),
PI3Kinase, and MAP kinase in diabetic rats [23].
PKC inhibitors decrease hyperfiltration and proteinuria in animal models. (See 'Inhibitors of PKC' below.)
Multiple PKC isoform(s) contribute to the pathogenesis of diabetic nephropathy. Experiments with isoformspecific knockout mice suggest that activation of PKCalpha underlies the development of albuminuria and that
of PKCbeta contributes to glomerular hypertrophy and mesangial expansion [15].
Both isoforms appear to contribute to reactive oxygen species generation, which plays a substantive pathogenic
role in the progression of diabetic nephropathy [15,24-26].
Role of PKC in extrarenal complications Hyperglycemia-induced increases in PKC activity have been
observed in nonrenal tissue including retina, endothelial, smooth muscle cells, monocytes and macrophages
and cardiac tissue [3,27-30].
Animal studies have suggested that increased PKC activity contributes to atherosclerosis, cardiomyopathy,
diabetic retinopathy and diabetic neuropathy [3].
Hyperglycemia-induced PKC activation appears to contribute to endothelial dysfunction by increasing
expression of vascular endothelium growth factor (VEGF), thromboxane and endothelin, and decreasing levels
of nitric oxide (NO) and prostacyclin resulting in increases in vasoconstriction and permeability [3,31,32].
Extracellular matrix synthesis, fibrosis, dysregulation of cytokines and monocyte activation and impaired insulinstimulated glucose transport in muscle may all result from PKC activation [3,33].

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The identification of compounds that inhibit the PKC signaling pathway and block expression of PKC-regulated
genes may lead to novel therapeutic approaches to prevent and/or treat diabetic complications [34].
GENETICS Mutations that alter the expression or activity of protein kinases may underlie both abnormalities
in glucose metabolism and the predisposition to vascular complications of diabetes [35-39]. (See "Pathogenesis
of type 2 diabetes mellitus".)
Mutations that increase the activity of protein kinase C (PKC) isoforms may enhance susceptibility to diabetic
nephropathy in humans. This was suggested by the following two studies that showed an association of
PKCbeta1 single-nucleotide polymorphisms (SNPs) and diabetic nephropathy:
Nine PKCbeta1 SNPs were identified among patients who had type 1 diabetes and diabetic nephropathy
[40]. The frequency of each SNP was compared among case patients (defined as patients with type 1
diabetes and persistent proteinuria or end-stage renal disease (ESRD) as a result of diabetic
nephropathy) and control subjects (defined as patients with type diabetes for >15 years and who have an
albumin-to-creatinine ratio <17 mg/g for men, and <25 mg/g for women on spot urine specimens). The
frequency of two SNPs in the promoter region was greater among case patients compared with control
patients. The association was stronger among those who had a duration of diabetes less than 24 years.
Eighteen common SNPs were genotyped in 1172 Chinese patients without renal disease who were
recruited from 1995-1998 and compared with 1049 patients with early onset type 2 diabetes without renal
disease who were recruited after 1998 [41]. After a mean of 7.9 years, 90 patients (7.7 percent)
progressed to ESRD. ESRD was associated with four common SNPs.
INHIBITORS OF PKC Therapies aimed at lowering protein kinase C (PKC) may be beneficial in slowing the
progression of diabetic nephropathy, as shown in animal studies; however, studies in humans to date are rather
inconclusive in this regard [42,43]. The most widely studied isoform-specific PKC inhibitor is ruboxistaurin
mesylate, which is highly specific for PKCbeta isoforms [44]. Ruboxistaurin has been examined in animal
models of diabetes mellitus and a few pilot studies in humans [45].
Animal studies of ruboxistaurin The effects of ruboxistaurin on diabetic neuropathy, vascular permeability
and renal function have been studied in multiple animal models:
Two weeks of treatment with ruboxistaurin completely reversed the diabetes-induced reduction in sciatic
motor and saphenous sensory nerve conduction velocity (NCV) in streptozotocin (STZ)-induced diabetic
rats [46]. When combined with the antioxidants vitamin E or alpha-lipoic acid, motor and sensory NCV and
sciatic nerve perfusion improved to the nondiabetic range, demonstrating synergism between PKCbeta
and blockers of oxidative stress.
The topical application of ruboxistaurin to newly grown vessels in granulation tissue blocked glucoseinduced increases in both blood flow and permeability (figure 2) [47]. Oral administration of ruboxistaurin
for eight weeks prevented diabetes-induced increases in albumin permeation in the retina, nerve, and
aorta, but not in muscle or brain of diabetic rats, an effect possibly mediated by inhibition of transcription
factor binding to specific PKC-regulated genes that are involved in vascular function.
The oral administration of ruboxistaurin was associated with reversal of glomerular hyperfiltration (from 4.6
mL/min to the normal range of 3.0 0.2 mL/min) and reduction of urinary albumin excretion (11.7 to 4.9
mg/day [normal 1.6 mg/day]) in diabetic rats [48]. This occurred without a change in glycated hemoglobin
or DAG content in the retina or glomeruli.
Ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced
glomerular transforming growth factor (TGF)-beta1 and extracellular matrix protein production in the STZ
rat, Lepr(db)/Lepr(db) mouse, and STZ-Ren-2 rat models of diabetes [49]. Improvements were also noted
in mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis, and renal function.

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Ruboxistaurin significantly attenuated increases in PKC-induced osteopontin expression in tubular

epithelial cells of the renal cortex, macrophage recruitment and tubulointerstitial injury associated with
activity of TGF-beta in the Ren-2 diabetic rats [50].
Human studies of ruboxistaurin
Orally administered ruboxistaurin did not prevent the progression of retinopathy in initial clinical trials of
moderately severe to very severe nonproliferative diabetic retinopathy [51]. (See "Diabetic retinopathy:
Prevention and treatment", section on 'Nonproliferative diabetic retinopathy'.)
Ruboxistaurin stabilized the progression of nephropathy in 123 patients with type 2 diabetes and early
diabetic nephropathy (albumin-to-creatinine ratios of 200 to 2000 mg/gm and serum creatinine 1.7 mg/dL
[150 micromol/L] in women, and 2.0 mg/dL [177 micromol/L] in men) who were on stable doses of
angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) [52]. Patients
were randomly assigned to receive ruboxistaurin, 32 mg/day, or placebo. After one year, treatment with
ruboxistaurin was associated with a reduction in albuminuria and stabilization of estimated glomerular
filtration rate (eGFR), with no change in albuminuria and worsening of eGFR in the placebo group. There
was no difference between groups in mean blood pressure at baseline and at the end of the study.
The effect of ruboxistaurin on long-term (greater than one year) renal outcomes was evaluated in a
secondary analysis of three diabetic retinopathy trials [53]. During median follow-up at 33 to 39 months, no
differences in kidney outcomes were observed between ruboxistaurin and placebo. The result of a
prospective study of the effect of ruboxistaurin versus placebo in 9 diabetic and 11 control patients was
also disappointing; no difference was found between cohorts in peripheral nerve conduction velocity or
symptoms of sensory neuropathy [54]. Adding to disappointment in the use of ruboxistaurin in diabetes is
a randomized, 14-day double-blind, crossover, placebo-controlled trial of ruboxistaurin mesylate in 13
subjects with type 2 diabetes without evidence of cardiovascular disease and 15 healthy control subjects.
No significant change in endothelium-dependent or endothelium-independent vasodilation or blood-based
markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress was noted in either diabetic
or healthy subjects [55].
Much larger trials are required before determining the potential clinical role of this agent [56]. Ruboxistaurin is in
phase 2 clinical trials in diabetic retinopathy and cardiac ventricular hypertrophy cardiomyopathy.
Other PKC inhibitors The treatment of diabetic rats with d-alpha-tocopherol, which decreases DAG and
inhibits PKC activation, prevents glomerular hyperfiltration and minimizes the development of proteinuria (2.4
versus 9.1 mg/day in control diabetic rats [versus 1.2 mg/day in nondiabetic rats]) [42].
Elevated cytosolic glucose promotes the accumulation of glyceraldehyde 3-phosphate, which activates PKC [4].
Large doses of thiamine and the thiamine monophosphate derivative, benfotiamine decreased the formation of
glyceraldehyde 3-phosphate and mitigated PKC activation in an experimental model of diabetes [57]. This was
associated with a decrease in the development of moderately increased albuminuria (the new term for what
was previously called "microalbuminuria" [58]) and prevention of hyperfiltration, without a change in elevated
plasma glucose concentration and glycated hemoglobin.
SUMMARY
Increased activity of protein kinase C (PKC) appears to contribute to the micro- and macrovascular
complications of diabetes mellitus. Mechanisms by which this occurs likely include PKC-induced changes
in vascular permeability, angiogenesis, cell growth and apoptosis, vessel dilation, cytokine activation,
basement membrane thickening and extracellular matrix expansion. (See 'Introduction' above and 'Role of
PKC in vascular complications' above.)
Multiple PKC isoforms appear to be involved in the development of diabetic nephropathy. Studies of
isoform-specific knockout mice suggest that PKCalpha contributes to albuminuria and PKCbeta to

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glomerular hypertrophy and mesangial expansion. Both isoforms may play a role in the generation of
reactive oxygen species. (See 'Diabetic nephropathy' above.)
Increased PKC activity may also underlie the development of atherosclerosis, cardiomyopathy, diabetic
retinopathy and diabetic neuropathy. (See 'Role of PKC in extrarenal complications' above.)
Mutations that alter expression or activity of PKC may enhance susceptibility to diabetic nephropathy in
humans. Single-nucleotide polymorphisms (SNPs) of the PKCbeta1 gene have been associated with
proteinuria and with end-stage renal disease (ESRD). (See 'Genetics' above.)
The clinical benefit of therapies aimed at lowering PKC activity in preventing or delaying the complications
of diabetes mellitus is not clear at this time. (See 'Inhibitors of PKC' above.)
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GRAPHICS
Mechanisms of hyperglycemia-induced vascular
complications

Flow diagram showing how too much glucose may lead to the long-term
complications of diabetes.
AGE: advanced glycosylation endproducts; DAG: diacylglycerol; PKC: protein
kinase C.
Graphic 61356 Version 2.0

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Action of protein kinases

Schematic representation of the action of protein kinases. Phosphates

are transferred from ATP molecules onto target molecules by protein
kinases; these phosphates are then removed by protein phosphatases.
Graphic 78694 Version 1.0

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Protein kinase C inhibition protects against

hyperglycemia-induced vascular dysfunction

Effect of the PKC inhibitor LY290181 on vascular dysfunction in skin

chamber granulation tissue induced by elevated glucose levels in
nondiabetic rats. Skin chamber granulation tissue was treated with
either 5 or 30 mmol/L of glucose alone or 30 mmol/L of glucose plus 20
to 50 mol/L of LY290181 twice daily for seven days. Exposure to the
high glucose solution increased both blood flow and vascular
permeability; these effects were prevented by LY290181.
Graphic 73671 Version 1.0

Disclosures
Disclosures: Eli A Friedman, MD Nothing to disclose. Richard J Glassock, MD, MACP Consultant/Advisory Boards: Bristol-MyersSquibb [lupus nephritis (Abatacept)]; Abbvie [lupus nephritis (no product)]; Sanofi-Genzyme [FSGS (Fresolimumab)]; Chemocentryx
[diabetes (CCR2 antagonist)]; QuestCor [nephrotic syndrome (ACTH Gel)]; Eli Lily [kidney disease (no product)]; Astellas [kidney
disease (Tacrolimus)]. Speaker's Bureau: Genentech [vasculitis (Rituximab)]. Other Financial Interest: Karger [editor]; AAKP [patients
with kidney disease]; American Renal Associates [dialysis]. Equity Ownership/Stock Options: Reata Stock [diabetes]. David M Nathan,
MD Nothing to disclose. John P Forman, MD, MSc Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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