Diabetic Neuropathy - Pathology
Protein kinase C -
updated: 15 March 2008
Protein Kinase C
Lodewijk V. Dekker
Protein Kinase C is a pivotal component of the mechanism that allows a cell to respond to its changing environment. In this book, the most significant advances in recent basic research on Protein Kinase C are explained...
Online - Book
The role of protein kinase C activation and the vascular complications of diabetes
Pharmacol Res. 2007 Jun;55(6):498-510. Epub 2007 May
Das Evcimen N, King GL.
Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, and by resistance to insulin's effects. Such a deficiency results in increased concentrations of glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of diabetes mellitus: Type 1 diabetes (insulin-dependent diabetes, IDDM or juvenile onset diabetes) and Type 2 diabetes (non-insulin-dependent diabetes, NIDDM or adult-onset). Chronic hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C (PKC) isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the retinal, renal, neural and cardiovascular tissues in diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis, cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-ATPase, cPLA(2), PI3Kinase and MAP kinase. Inhibition of PKC, especially the beta1/2 isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that ruboxistaurin, a PKCbeta isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several isoforms is likely to be responsible for some of the pathologies in diabetic retinopathy, nephropathy and cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease with very little side effects.
Publication Types:
Online - Abstract
Protein kinase C activation and the development of diabetic complications
Diabetes. 1998 Jun;47(6):859-66
Koya D, King GL.
Recent studies have identified that the activation of protein kinase C (PKC) and increased diacylglycerol (DAG) levels initiated by hyperglycemia are associated with many vascular abnormalities in retinal, renal, and cardiovascular tissues. Among the various PKC isoforms, the beta- and delta-isoforms appear to be activated preferentially in the vasculatures of diabetic animals, although other PKC isoforms are also increased in the renal glomeruli and retina. The glucose-induced activation of PKC has been shown to increase the production of extracellular matrix and cytokines; to enhance contractility, permeability, and vascular cell proliferation; to induce the activation of cytosolic phospholipase A2; and to inhibit Na+-K+-ATPase. The synthesis and characterization of a specific inhibitor for PKC-beta isoforms have confirmed the role of PKC activation in mediating hyperglycemic effects on vascular cells, as described above, and provide in vivo evidence that PKC activation could be responsible for abnormal retinal and renal hemodynamics in diabetic animals. Transgenic mice overexpressing PKC-beta isoform in the myocardium developed cardiac hypertrophy and failure, further supporting the hypothesis that PKC-beta isoform activation can cause vascular dysfunctions. Interestingly, hyperglycemia-induced oxidative stress may also mediate the adverse effects of PKC-beta isoforms by the activation of the DAG-PKC pathway, since treatment with D-alpha-tocopherol was able to prevent many glucose-induced vascular dysfunctions and inhibit DAG-PKC activation. Clinical studies are now in progress to determine whether PKC-beta inhibition can prevent diabetic complications.
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Online - Article
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