ALDOSE REDUCTASE AND DIABETIC COMPLICATIONS

醛糖还原酶和糖尿病并发症

• 批准号: 2139731
• 负责人: SATISH K SRIVASTAVA
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2139731
• 关键词: ALDOSE; REDUCTASE; DIABETIC; COMPLICATIONS

DESCRIPTION: (Investigator's Abstract). Prolonged diabetes causes major complications in tissues which do not require insulin for transport of glucose, including hyperglycemia-induced neuropathy, retinopathy, nephropathy, epitheliopathy, and cataractogenesis. However, the mechanisms of hyperglycemia-induced cell injury are poorly understood. The first enzyme of the polyol pathway, aldose reductase (AR), has been implicated in diabetic complications because use of aldose reductase inhibitors (ARIs) prevents, reduces, or, to some extent, reverses hyperglycemia-induced cataractogenesis, neuropathy, and retinopathy. Increased AR activity in hyperglycemia has been attributed to activation and/or induction of the enzyme. However, neither the mechanisms of induction nor of activation are well understood. In addition, all the ARIs presently known inhibit both AR and aldehyde reductase, and both enzymes have overlapping substrate specificities. Aldehyde reductase may be important for reducing biogenic amines and a number of dicarbonyl compounds. Therefore, for understanding and managing diabetic complications, it is necessary to elucidate the physicochemical properties of AR and its regulation and physiological roles, along with the properties of aldehyde reductase. We propose to continue our studies on the structural and kinetic properties of AR and aldehyde reductase, and on the regulation of AR under normo-glycemic and hyperglycemic conditions. We will determine the chemical catalytic mechanisms of aldehyde reduction by these enzymes, their mechanisms of inhibitor and substrate interactions, and the sequences of their substrate binding sites. The residues involved in substrate and inhibitor binding, inactivation of aldose reductase and in the chemical reactions will be studied by using site directed mutagenesis. The AR activity increases in hyperglycemia, and the reaction kinetics and inhibitor sensitivity also change. The roles of oxidation, glycation and induction will be examined to understand the mechanism(s) of activation, deactivation and increased transcription of AR during hyperglycemia. We will use a hyperglycemic animal model and cultured neuroblastoma cells to assess the contributions of oxidative stress to tissue injury, perhaps caused by increased free radicals and/or decreased defense capacity against oxidants and polyols. Our studies will help in understanding the role of AR in the etiology of diabetic complications, and will provide a logical approach to treating or preventing the development of such complications.

描述：（研究者摘要）。 长期糖尿病会导致 不需要胰岛素转运的组织中的并发症 葡萄糖，包括高血糖诱导的神经病变，视网膜病变， 肾病、上皮病和白内障形成。 但 高血糖诱导的细胞损伤的机制知之甚少。 多元醇途径的第一种酶，醛糖还原酶（AR），已经被发现。 与糖尿病并发症有关，因为使用醛糖还原酶 抑制剂（阿里斯）可预防、减少或在一定程度上逆转 高血糖诱导的白内障发生、神经病和视网膜病。 高血糖症中AR活性增加归因于激活 和/或酶的诱导。然而， 诱导和活化都是很好理解的。 此外，所有 目前已知的阿里斯抑制AR和醛还原酶，并且两者均 酶具有重叠的底物特异性。 醛还原酶可能 对于减少生物胺和一些二羰基化合物是重要的， 化合物. 因此，为了了解和管理糖尿病 并发症，有必要阐明理化 AR的特性及其调节和生理作用，沿着 醛还原酶的性质。 我们建议继续我们的 AR和醛的结构和动力学性质研究 还原酶，以及在正常血糖和 高血糖状况。 我们将确定化学催化剂 这些酶的醛还原机制， 抑制剂和底物的相互作用，以及它们的序列 底物结合位点。 底物中的残基和 抑制剂结合，醛糖还原酶的失活， 将通过使用定点诱变来研究反应。 的AR 高血糖时活性增加，反应动力学和 抑制剂敏感性也改变。氧化、糖化和 将检查诱导以理解激活的机制， 在高血糖期间，AR失活和转录增加。 我们将使用高血糖动物模型和培养的神经母细胞瘤 细胞来评估氧化应激对组织损伤的贡献， 可能是由自由基增加和/或防御能力下降引起的 抗氧化剂和多元醇的能力。 我们的研究将有助于 了解AR在糖尿病并发症病因学中的作用， 并将为治疗或预防 这些并发症的发展。