Studies of Rat and Human Retinas Predict a Role for the Polyol Pathway in Human Diabetic Retinopathy

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. Diabetes 53: 2404 -2411, 2004 M ost cells of the retina are affected by the metabolic abnormalities of diabetes (1), but the sight-threatening manifestations of diabetic retinopathy are ultimately attributable to capillary damage. Abnormal permeability of barrier capillaries can cause macular edema, and capillary closure causes ischemia and unregulated angiogenesis (2). The current means to maintain a normal metabolic status in diabetic patients are imperfect, and they are successful in only a fraction of patients. It would thus be desirable to complement antidiabetic therapy with drugs that target processes specific to the complications of diabetes.The polyol pathway of glucose metabolism becomes active when intracellular glucose levels are elevated (3,4). Aldose reductase, the first and rate-limiting enzyme in the pathway, reduces glucose to sorbitol using NADPH as a cofactor; sorbitol is then metabolized to fructose by sorbitol dehydrogenase, which uses NAD ϩ as a cofactor. The polyol pathway is both a "dream" and a "dread" target when devising strategies to prevent diabetic retinopathy. The pathway is a dream target because its activation is immediately linked to hyperglycemia, generates various types of cellular stress (4 -6), and occurs prominently in the tissues that develop complications (3-6), thus promising returns beyond retinopathy. In addition, polymorphisms of the aldose reductase gene may help predict individual susceptibility to retinopathy and other microvascular complications (7), and the enzymatic function of aldose reductase can be specifically inhibited (4) with the expecta...

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

“…It progressively increased with the prolongation of exposure of cultured bovine retinal pericytes and endothelial cells to high glucose levels. Our findings are consistent with other studies suggesting that AR inhibition suppresses early apoptosis in the neural retina of diabetic rats (36,40) as well as high glucose-exposed cultured retinal pericytes (61). Furthermore, they support and complement our previous findings of the inhibitory effect of the ARI zopolrestat on caspase-3 activation, an indirect measure of cell death, in high glucoseexposed cultured retinal endothelial cells (62).…”

“…In particular, fidarestat treatment counteracted retinal glial activation manifest in GFAP accumulation. The latter is consistent with previous studies with other ARIs, sorbinil (40) and ARI-809 (36). It has been hypothesized that retinal neurodegenerative changes including increased glial cell reactivity and microglial activation, together with altered glutamate metabolism and premature apoptosis, are a critical component of diabetic retinopathy (41).…”

Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy

“…Activation of the complement cascade can both compound and initiate thrombosis, leucostasis and apoptosis, all of which are processes involved in vascular lesions of diabetic retinopathy. Interestingly, it has been reported that the inhibition of aldose reductase prevents the activation of complement in the wall of retinal vessels and decreased levels of complement inhibitors in diabetic rats [31]. Therefore, since several ways of specifically manipulating the complement system already exist, they could represent a possible therapeutic approach in diabetic retinopathy.…”

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

“…Such excess aldose reductase activity can be a mechanism for human diabetic retinopathy [20]. The polyol pathway of glucose metabolism becomes active when intracellular glucose levels are elevated.…”