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 hypergly cemia are associated with many vascular abnormalities in retinal, rena l, and cardiovascular tissues. Among the various PKC isoforms, the bet a- and delta-isoforms appear to be activated preferentially in the vas culatures of diabetic animals, although other PKC isoforms are also in creased in the renal glomeruli and retina. The glucose-induced activat ion of PKC has been shown to increase the production of extracellular matrix and cytokines; to enhance contractility, permeability, and vasc ular cell proliferation; to induce the activation of cytosolic phospho lipase A(2); and to inhibit Na+-K+-ATPase. The synthesis and character ization of a specific inhibitor for PKC-beta isoforms have confirmed t he role of PKC activation in mediating hyperglycemic effects on vascul ar cells, as described above, and provide in vivo evidence that PKC ac tivation could be responsible for abnormal retinal and renal hemodynam ics in diabetic animals. Transgenic mice overexpressing PKC-beta isofo rm in the myocardium developed cardiac hypertrophy and failure, furthe r 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 t he activation of the DAG-PKC pathway, since treatment with D-alpha-toc opherol 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 complica tions.