MECHANISM OF SUGAR CATARACT FORMATION IN LENS CELLS

点击翻译按钮获取中文摘要

DESCRIPTION: (Investigator's Abstract). Bovine lens epithelial cells (BLECs) exposed to hypergalactosemic or hyperglycemic conditions provide a convenient physiological surrogate with which to examine the mechanisms involved in cataract formation and the early onset of diabetic complications in an in vivo cell culture model. The precise role in which high ambient sugars play in the onset of diabetic complications is obscure but cannot be overlooked as the administration of aldose reductase inhibitors prevent or reverse the aforementioned "complications". However, any model which discusses the onset of diabetic complications via polyol accumulation must also consider that many tissues do not accumulate sorbitol to an adequately high enough level to exert an osmotic effect. Hence any explanation must provide a mechanistic basis for the involvement of the aldose reductase reaction but also discuss this in terms of low concentration of accumulated polyols. This study will integrate the "polyol" hypothesis with the "myo-inositol depletion" hypothesis in a manner more applicable to the situation found in the diabetic human lens. The specific aims of this grant proposal are to determine: (1) the mechanism of reduction in activity of glutathione synthetase as mediated by exposure of cultured bovine lens epithelial cells to hyperglycemic conditions. (2) whether glutathione depletion resulting from the reduction in activity of glutathione synthetase promotes decreased myo-inositol uptake and a reduction in Na+-K+-ATPase activity, (3) if an alteration in Na+-membrane permeability or a reduction in Na+-K+-ATPase activity results in an accumulation of intracellular sodium which leads to an influx of extracellular water and a decrease in myo-inositol uptake, (4) if a decrease in myo-inositol uptake and/or Na+-K+-ATPase activity disturbs normal phosphoinositide turnover resulting in the compromised release of the second messengers, lns(l,4,5)P3 and diacylglycerol (DAG), (5) if a decrease in released intracellular DAG adversely affects protein kinase C(PKC) activity further destabilizing Na+-K+-ATPase activity. (6) whether hyperglycemic exposure leads to dysfunctional lipid metabolism and decreased prostaglandin product formation, and (7) if the suppression of PGH synthase activity as mediated by hyperglycemic conditions, augments alternative arachidonate oxygenated metabolites, in particular, 12 (R)-HETE, a known inhibitor of Na+-K+-ATPase. Hence, a biochemical deficit at any one of these interrelated levels could potentially contribute to cataract formation or the onset of diabetic complications. Moreover, our working hypothesis does not rely on a high concentration of intracellular polyol to explain the influx of water associated with hyperglycemic exposure, but rather assumes that the accumulation of intracellular sodium leads to ionic imbalance and cell hydration and swelling. The lens epithelial cell system will provide a useful model for determining the biochemical deficits resulting from sustained hypergalactosemia or hyperglycemia and regulation by aldose reductase inhibitors.