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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 A^sub 2^; 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 DAGPKC activation. Clinical studies are now in progress to determine whether PKC-beta inhibition can prevent diabetic complications. Diabetes 47:859-866, 1998
cGMP, cyclic guanosine monophosphate; cPLA^sub 2^, cytosolic phospholipase A^sub 2^; DAG, diacylglycerol; ECM, extracellular matrix; ET-1, endothelin-1; GFR, glomerular filtration rate; iNOS, inducible nitric oxide synthase; NO, nitric oxide; PC, phosphatidylcholine; PGE^sub 2^,prostaglandin E^sub 2^; PI, phosphatidylinositide; PKC, protein kinase C: PLC, phospholipase C; PLD, phospholipase D; TGF-Beta, transforming growth factor-beta; VEGF, vascular endothelial growth factor; VPF, vascular permeability factor
Hyperglycemia induces a bewildering list of changes in vascular or neuronal cells in animal models of diabetes or diabetic patients. The pleotypic nature of the changes is not surprising, since the flux of glucose and its metabolites are known to affect many cellular pathways. The main challenge in this area has been to identify those hyperglycemia-induced biochemical changes that are significant in causing vascular dysfunctions and pathologies. Multiple theories have been proposed to explain the pathogenesis of the various complications involving retina, glomeruli,...