Aldose reductase/polyol inhibitors for diabetic retinopathy

Diabetic retinopathy is the most common microvascular complication of diabetes and the most severe of diabetic ocular complications. This review describes retinal changes at different stages of diabetic retinopathy and risk factors associated with this devastating disease. Special attention is focused on aldose reductase, the first enzyme of the sor-bitol pathway of glucose metabolism. The current knowledge on the enzyme localization in the retina, and the role for increased aldose reductase activity in retinal capillary cell loss and formation of acellular capillaries, capillary basement membrane thickening, increased vascular permeability and disruption of blood-retinal barrier, and increased leukocyte adhesion to endothelial cells associated with early diabetic retinopathy, as well as neovascularization associated with advanced (proliferative) diabetic retinopathy, gained through the experimental studies in animal models of diabetes and ga-lactose feeding, is described in detail. The review also analyzes the potential mechanisms underlying aldose reductase involvement in pathogenesis of diabetic retinopathy, and discusses interactions between aldose reductase and other patho-genetic factors such as formation of advanced glycation end-products, oxidative-nitrosative stress, protein kinase C, mito-gen-activated protein kinase, and poly(ADP-ribose) polymerase activations, inflammation, and growth factor imbalances. A detailed analysis of clinical diabetic retinopathy trials of aldose reductase inhibitors is also provided.