The Role of Protein Kinase C in Diabetic Retinopathy

Abstract

The protein kinase C (PKC) molecule is part of a serine/threonine kinase family that catalyzes phosphorylation of key proteins involved in signal transduction. Conventional and novel PKC isoforms are upregulated by diacylglycerol (DAG), which in turn is increased by the hyperglycemia of diabetes. PKC isoforms are differentially expressed and activated in tissues throughout the body, including the aorta, kidney, heart, monocytes, and retina, but not in the brain or peripheral nerves. In the retina, PKC activation is associated with changes in retinal blood flow, possibly through effects on retinal pericytes, the expression of endothelium-derived growth factors, and/or leukostasis. The activation of PKC may also lead to basement membrane and extracellular matrix alterations within the retinal vasculature. Increases in retinal vascular permeability and angiogenesis are seen with PKC activation related to its actions on vascular endothelial growth factor. Inhibition of PKC, particularly PKC-beta isoforms, appears to ameliorate many of these effects on the retinal vasculature. Ruboxistaurin is a PKC inhibitor with a high affinity for PKC-beta isoforms. Human clinical studies with this drug are ongoing, but trials have already demonstrated its efficacy in preventing vision loss, decreasing the need for laser treatment, and decreasing the progression of macular edema in patients with diabetes. 208 Prakash et al.