MECHANISM OF SUGAR CATARACT FORMATION IN LENS CELLS

晶状体细胞中糖类白内障的形成机制

• 批准号: 3260722
• 负责人: Patrick Ross Cammarata
• 金额: $ 14.29万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3260722
• 关键词: acid aminoacid ligase; adenosinetriphosphatase; aldehyde reductase; arachidonate; cataract; cow; diabetic ophthalmopathy; diacylglycerols; eicosanoid metabolism; eicosanoids; epithelium; hyperglycemia; intraocular fluid; lens; lipid metabolism; membrane permeability; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; prostaglandins; protein kinase C; second messengers; sorbitol; tissue /cell culture

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.

描述：（研究者摘要）。 牛透镜上皮细胞 （BLEC）暴露于高半乳糖血症或高血糖状况提供了 方便的生理替代品，用于检查机制 参与白内障的形成和糖尿病的早期发病 在体内细胞培养模型中的并发症。 其中的确切作用 高糖在糖尿病并发症发病中的作用尚不清楚 但不能忽视的是， 抑制剂预防或逆转上述“并发症”。 然而，在这方面， 任何讨论通过多元醇引发糖尿病并发症的模型 积累还必须考虑到许多组织不积累 山梨糖醇至足够高的水平以发挥渗透作用。 因此，任何解释都必须提供一个机械的基础， 但也讨论了这方面的低 积累的多元醇的浓度。 本研究将整合 “多元醇”假说与“肌醇耗竭”假说在一个 这种方式更适用于糖尿病患者透镜中的情况。 这项拨款建议的具体目的是确定：（1） 谷胱甘肽合成酶活性降低的机制 培养的牛透镜上皮细胞暴露于高血糖 条件 (2)是否由于还原导致谷胱甘肽耗竭 谷胱甘肽合成酶的活性促进降低肌醇 摄取和Na+-K+-ATP酶活性的降低，（3）如果 Na+-膜渗透性或Na+-K+-ATP酶活性降低导致 细胞内钠离子的积累， 细胞外水和减少肌醇摄取，（4）如果 肌醇摄取和/或Na+-K+-ATP酶活性的降低 正常的磷酸肌醇周转，导致 第二信使，lns（1，4，5）P3和二酰基甘油（DAG），（5）如果 释放的细胞内DAG的减少不利地影响蛋白激酶 C（PKC）活性进一步使Na+-K+-ATP酶活性不稳定。 (6)是否 高血糖暴露导致脂质代谢功能障碍， 前列腺素产物形成减少，和（7）如果抑制 由高血糖条件介导的PGH合酶活性， 替代的花生四烯酸含氧代谢物，特别是12 （R）-HETE，一种已知的Na+-K+-ATP酶抑制剂。 因此，生化缺陷 在这些相互关联的层面上， 白内障形成或糖尿病并发症的发作。 而且我们 工作假设不依赖于高浓度的细胞内 多元醇来解释与高血糖相关的水流入 暴露，而是假设细胞内钠的积累 导致离子失衡和细胞水合作用和肿胀。 该透镜 上皮细胞系统将提供一个有用的模型， 持续性高半乳糖血症导致的生化缺陷，或 高血糖和通过醛糖还原酶抑制剂调节。