[Mechanism of diabetes-induced microvascular damage and therapeutic potential of ROCK inhibition]

Abstract

The rapid increase in diabetic retinopathy (DR), a common ocular complication of diabetes mellitus, necessitates the development of new therapeutic strategies for the amelioration and treatment of DR, especially in the earlier stages. In the present study, involvement of the Rho/Rho-kinase (ROCK) pathway in diabetic microvasculopathy and the therapeutic potential of fasudil, a selective ROCK inhibitor, were investigated. Retinal microvascular damage secondary to increased leukocyte adhesion substantially contributes to DR in its early stages. Significant Rho/ ROCK activation was observed in the retinal microvasculature of diabetic rats. The ROCK inhibitor, fasudil, protects the vascular endothelium by inhibit- ing leukocyte adhesion and reducing leukocyte-induced endothelial injury mediated through the restoration of endothelial nitric oxide synthase activity, in the retinas of diabetic rats. In co-culture assay of DR leukocytes and microvascular endothelial cells, we investigated the protective mechanisms of fasudil on endothelial damage using L-NAME, an inhibitor of nitric oxide synthase. Leukocytes from DR patients caused endothelial apoptosis via Fas/ FasL interaction, which was significantly reduced by a ROCK inhibition dependent on nitric oxide. The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy and ROCK inhibition may become a new strategy in the amelioration and treatment of DR, especially in its early stages.