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.