Studies of Rat and Human Retinas Predict a Role for the Polyol Pathway in Human Diabetic Retinopathy Zeina Dagher , Yong Seek Park , Veronica Asnaghi , Todd Hoehn , Chiara Gerhardinger and Mara Lorenzi Department of Ophthalmology, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts Address correspondence and reprint requests to Mara Lorenzi, MD, Harvard Medical School, Schepens Eye Research Institute, 20 Staniford St., Boston, MA 02114. E-mail: lorenzi{at}vision.eri.harvard.edu Abstract The polyol (sorbitol) pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the polyol pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the polyol pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy. DMEM, Dulbecco’s modified Eagle’s medium mAb, monoclonal antibody MAC, membrane attack complex NSE, neuron-specific enolase, PECAM-1, platelet endothelial cell adhesion molecule-1 RIPA, radioimmunoprecipitation assay TUNEL, transferase-mediated dUPT nick-end labeling vWf, von Willebrand factor Footnotes Y.S.P. and V.A. contributed equally to this study. M.L. has received an honorarium from Pfizer. Accepted May 26, 2004. Received January 22, 2004. DIABETES