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.