Inhibition of protein kinase C δ attenuates blood-retinal barrier breakdown in diabetic retinopathy

Abstract

Vision loss in diabetic retinopathy is due to macular edema characterized by increased vascular permeability, which involves phosphorylation associated with activation of protein kinase C (PKC) isoforms. Herein, we demonstrated PKC δ inhibition could prevent blood-retinal barrier breakdown in diabetic retinopathy. Increased vascular permeability of diabetic retina was accompanied by a decrease of zonula occludens (ZO)-1 and ZO-2 expression. In diabetic retina and advanced glycation end product-treated human retinal microvascular endothelial cells, vascular leakage and loss of ZO-1 and ZO-2 on retinal vessels were effectively restored or prevented with treatment of rottlerin, transfection of PKC-δ-DN, or siRNA for PKC δ. Interestingly, PKC δ translocated from cytosol to membrane in advanced glycation end producttreated human retinal microvascular endothelial cells, which was blocked by PKC δ inhibition. Taken together, PKC δ activation, related to its subcellular translocation, is involved in vascular permeability in response to diabetes, and inhibition of PKC δ effectively restores loss of tight junction proteins in retinal vessels. Therefore, we suggest that inhibition of PKC δ could be an alternative treatment to blood-retinal barrier breakdown in diabetic retinopathy. Copyright © American Society for Investigative Pathology.