Protein kinase C activation and the development of diabetic complications.
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.
Koya
D
D
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
King
G L
GL
D000818:Animals; D002199:Capillary Permeability; D009202:Cardiomyopathies / Q000209:etiology; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000201:enzymology / Q000503:physiopathology*; D004789:Enzyme Activation; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology; D051379:Mice; D009389:Neovascularization, Pathologic; D011493:Protein Kinase C / Q000378:metabolism*; D012039:Regional Blood Flow
D011493:Protein Kinase C