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: 2159464
• 负责人: Patrick Ross Cammarata
• 金额: $ 14.54万
• 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 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2159464
• 关键词: acid aminoacid ligase; 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; sodium potassium exchanging ATPase; 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：（研究者的摘要）。 牛透镜上皮细胞 （BLEC）暴露于高乳术或高血糖状况的（可提供） 方便的生理替代物可以检查机制 参与白内障形成和糖尿病的早期发作 体内细胞培养模型中的并发症。 确切的角色 糖尿病并发症发作中的高环境糖会晦涩难懂 但是不能忽略醛糖还原酶的给药 抑制剂预防或逆转上述“并发症”。 然而， 任何通过多元醇讨论糖尿病并发症发作的模型 积累还必须考虑许多组织不积聚 山梨糖醇足够高，以发挥渗透作用。 因此，任何解释都必须为参与提供机械基础 醛糖还原酶反应的反应，但也以低 累积多元醇的浓度。 这项研究将整合 用“肌醇耗竭”假设的“多元元”假设 方式更适用于糖尿病人类镜头中发现的情况。 该赠款提案的具体目的是确定：（1） 谷胱甘肽合成酶活性减少的机制，如 培养的牛透镜上皮细胞暴露于高血糖 状况。 （2）谷胱甘肽是否由还原引起 谷胱甘肽合成酶的活性促进肌醇降低 Na+-K+-ATPase活性的吸收和减少，（3）如果发生了变化 Na+ - 膜渗透性或Na+-K+-ATPase活性的降低 在细胞内钠的积累中，导致涌入 细胞外水和肌醇摄取摄取的降低，（4）如果 减少肌醇吸收和/或Na+-K+-ATPase活动干扰 正常的磷酸肌醇周转额，导致释放损害 第二个使者LNS（L，4,5）P3和二酰基甘油（DAG），（5）如果A 减少释放的细胞内DAG不利影响蛋白激酶 C（PKC）活性进一步破坏Na+-K+-ATPase活性。 （6）是否 高血糖暴露会导致功能失调的脂质代谢和 降低前列腺素产品的形成，（7）如果抑制 PGH合酶活性是由高血糖条件介导的，增强 替代蛛网膜氧化代谢产物，特别是12 （R）-HETE，Na+-K+-ATPase的已知抑制剂。 因此，生化赤字 在这些相互关联的层次中，任何一个都可能有助于 白内障形成或糖尿病并发症的发作。 而且，我们的 工作假设不依赖于高浓度的细胞内 多元元来解释与高血糖相关的水的涌入 暴露，而是假设细胞内钠的积累 导致离子失衡，细胞水合和肿胀。 镜头 上皮细胞系统将提供一个有用的模型来确定 持续性高乳酸血症或 高血糖和醛糖还原酶抑制剂调节。