Protein kinase C and the vascular complications of diabetes mellitus
- Eli A Friedman, MD
Eli A Friedman, MD
- Distinguished Teaching Professor of Medicine
- Downstate Medical Center, Brooklyn, New York
- Section Editors
- Richard J Glassock, MD, MACP
Richard J Glassock, MD, MACP
- Editor-in-Chief — Nephrology
- Section Editor — Glomerular Diseases
- Emeritus Professor
- The David Geffen School of Medicine at UCLA
- David M Nathan, MD
David M Nathan, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- Harvard Medical School
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".)
●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 .
●Increased activity of the hexosamine pathway, which may alter gene expression and protein function .
●Increased formation of advanced glycated end products (AGEs) , which may activate protein kinase C (PKC) isoforms . The mechanisms of oxidant-induced interaction between PKC isoforms and AGEs resulting in vascular disease are incompletely defined .
- Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
- Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 2010; 106:1319.
- Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414:813.
- Garay-Sevilla ME, Regalado JC, Malacara JM, et al. Advanced glycosylation end products in skin, serum, saliva and urine and its association with complications of patients with type 2 diabetes mellitus. J Endocrinol Invest 2005; 28:223.
- He Z, King GL. Protein kinase Cbeta isoform inhibitors: a new treatment for diabetic cardiovascular diseases. Circulation 2004; 110:7.
- Cai W, Torreggiani M, Zhu L, et al. AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular disease. Am J Physiol Cell Physiol 2010; 298:C624.
- Craven PA, Studer RK, Negrete H, DeRubertis FR. Protein kinase C in diabetic nephropathy. J Diabetes Complications 1995; 9:241.
- Koya D, Jirousek MR, Lin YW, et al. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 1997; 100:115.
- Craven PA, DeRubertis FR. Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose. J Clin Invest 1989; 83:1667.
- Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998; 47:859.
- Ways DK, Sheetz MJ. The role of protein kinase C in the development of the complications of diabetes. Vitam Horm 2000; 60:149.
- Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 Suppl 1:S30.
- Inoguchi T, Battan R, Handler E, et al. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci U S A 1992; 89:11059.
- Menne J, Meier M, Park JK, Haller H. Inhibition of protein kinase C in diabetic nephropathy--where do we stand? Nephrol Dial Transplant 2009; 24:2021.
- Karin M. The AP-1 complex and its role in transcriptional control by protein kinase C. In: Molecular Aspects of Cellular Regulation, Cohen P, Foulkes JG (Eds) (Eds), Elsevier, New York 1991. p.235.
- Noh H, King GL. The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl 2007; :S49.
- Haneda M, Kikkawa R, Sugimoto T, et al. Abnormalities in protein kinase C and MAP kinase cascade in mesangial cells cultured under high glucose conditions. J Diabetes Complications 1995; 9:246.
- Chen S, Cohen MP, Lautenslager GT, et al. Glycated albumin stimulates TGF-beta 1 production and protein kinase C activity in glomerular endothelial cells. Kidney Int 2001; 59:673.
- Studer RK, Craven PA, DeRubertis FR. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. Diabetes 1993; 42:118.
- Ziyadeh FN, Fumo P, Rodenberger CH, et al. Role of protein kinase C and cyclic AMP/protein kinase A in high glucose-stimulated transcriptional activation of collagen alpha 1 (IV) in glomerular mesangial cells. J Diabetes Complications 1995; 9:255.
- Li X, Pabla N, Wei Q, et al. PKC-delta promotes renal tubular cell apoptosis associated with proteinuria. J Am Soc Nephrol 2010; 21:1115.
- Das Evcimen N, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res 2007; 55:498.
- Swaminathan S, Shah SV. Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease. Curr Opin Nephrol Hypertens 2008; 17:143.
- Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood) 2008; 233:4.
- Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest 2004; 34:785.
- Kunisaki M, Bursell SE, Clermont AC, et al. Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am J Physiol 1995; 269:E239.
- Hattori Y, Kawasaki H, Fukao M, Kanno M. Phorbol esters elicit Ca(2+)-dependent delayed contractions in diabetic rat aorta. Eur J Pharmacol 1995; 279:51.
- Haneda M, Koya D, Kikkawa R. Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway. Am J Kidney Dis 2001; 38:S178.
- Srivastava AK. High glucose-induced activation of protein kinase signaling pathways in vascular smooth muscle cells: a potential role in the pathogenesis of vascular dysfunction in diabetes (review). Int J Mol Med 2002; 9:85.
- Shiba T, Inoguchi T, Sportsman JR, et al. Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Physiol 1993; 265:E783.
- Wolf BA, Williamson JR, Easom RA, et al. Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels. J Clin Invest 1991; 87:31.
- Temofonte N, Sajan MP, Nimal S, et al. Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle. Diabetologia 2009; 52:60.
- Kuo DY, Yang SF, Chu SC, et al. Amphetamine-evoked changes of oxidative stress and neuropeptide Y gene expression in hypothalamus: regulation by the protein kinase C-delta signaling. Chem Biol Interact 2009; 180:193.
- O'Rahilly S, Barroso I, Wareham NJ. Genetic factors in type 2 diabetes: the end of the beginning? Science 2005; 307:370.
- Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 2004; 25:331.
- Wilkin TJ. Diabetes: 1 and 2, or one and the same? Progress with the accelerator hypothesis. Pediatr Diabetes 2008; 9:23.
- Perry JR, Frayling TM. New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care 2008; 11:371.
- Pleyer L, Egle A, Hartmann TN, Greil R. Molecular and cellular mechanisms of CLL: novel therapeutic approaches. Nat Rev Clin Oncol 2009; 6:405.
- Araki S, Ng DP, Krolewski B, et al. Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus. J Am Soc Nephrol 2003; 14:2015.
- Ma RC, Tam CH, Wang Y, et al. Genetic variants of the protein kinase C-beta 1 gene and development of end-stage renal disease in patients with type 2 diabetes. JAMA 2010; 304:881.
- Koya D, Lee IK, Ishii H, et al. Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol. J Am Soc Nephrol 1997; 8:426.
- Williams ME, Tuttle KR. The next generation of diabetic nephropathy therapies: an update. Adv Chronic Kidney Dis 2005; 12:212.
- Gassel M, Breitenlechner CB, König N, et al. The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A. J Biol Chem 2004; 279:23679.
- Gálvez MI. Rubosixtaurin and other PKC inhibitors in diabetic retinopathy and macular edema. Review. Curr Diabetes Rev 2009; 5:14.
- Cameron NE, Cotter MA. Effects of protein kinase Cbeta inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism. Diabetes Metab Res Rev 2002; 18:315.
- Birch KA, Heath WF, Hermeling RN, et al. LY290181, an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element. Diabetes 1996; 45:642.
- Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996; 272:728.
- Tuttle KR, Anderson PW. A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition. Am J Kidney Dis 2003; 42:456.
- Kelly DJ, Chanty A, Gow RM, et al. Protein kinase Cbeta inhibition attenuates osteopontin expression, macrophage recruitment, and tubulointerstitial injury in advanced experimental diabetic nephropathy. J Am Soc Nephrol 2005; 16:1654.
- PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 2005; 54:2188.
- Tuttle KR, Bakris GL, Toto RD, et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 2005; 28:2686.
- Tuttle KR, McGill JB, Haney DJ, et al. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin J Am Soc Nephrol 2007; 2:631.
- Brooks B, Delaney-Robinson C, Molyneaux L, Yue DK. Endothelial and neural regulation of skin microvascular blood flow in patients with diabetic peripheral neuropathy: effect of treatment with the isoform-specific protein kinase C beta inhibitor, ruboxistaurin. J Diabetes Complications 2008; 22:88.
- Beckman JA, Goldfine AB, Goldin A, et al. Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes. J Clin Endocrinol Metab 2010; 95:3783.
- Mehta NN, Sheetz M, Price K, et al. Selective PKC beta inhibition with ruboxistaurin and endothelial function in type-2 diabetes mellitus. Cardiovasc Drugs Ther 2009; 23:17.
- Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003; 52:2110.
- Chapter 1: Definition and classification of CKD. Kidney Int Suppl (2011) 2013; 3:19.