Cellular Pathophysiology of Acute Renal Failure

急性肾衰竭的细胞病理生理学

• 批准号: 6777033
• 负责人: JOEL M. WEINBERG
• 金额: $ 31.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777033
• 关键词: Krebs' cycle; acute renal failure; adenosine triphosphate; apoptosis; bioenergetics; cellular pathology; cytochrome c; electron transport; kidney cell; laboratory rabbit; membrane permeability; mitochondrial disease /disorder; mitochondrial membrane; renal ischemia /hypoxia; tissue /cell culture

Recently there has been a renewal of interest in mitochondrial dysfunction as a mediator of diverse forms of cell injury as a result of new insights into the mechanism for the mitochondrial permeability transition and recognition of the role of mitochondrial cytochrome c release in apoptosis. ATP production in the proximal tubule, a major site of injury during ischemic and toxic forms of acute renal failure, is especially sensitive to mitochondrial dysfunction because, depending on the segment, glcolysis is absent or minimal in proximal tubule cells in vivo. In studies during the present funding period, we have identified a mitochondrial lesion characterized by inhibition of electron transport in complex I associated with matrix condensation and partial deenergization as a functionally important form of mitochondrial injury during hypoxia/reoxygenation of freshly isolated rabbit proximal tubules that play a pivtal role in overall cellular recovery. The lesion: a) precedes the mitochondrial permeability transition and cytochrome c release; b) depresses energetic function of otherwise viable tubules for sustained periods; and c) is highly amenable to prevention and reversal by specific citric acid cycle metabolites that promote anaerobic pathways of intramitochondrial ATP production and electron transport or, under aerobic conditions, bypass the complex I block. The mitochondrial lesion is expressed both in freshly isolated tubules subjected to hypoxia/reoxygeation, and based on ultrastructural changes and modification by citric acid cycle metabolites, during ischemia/reperfusion in vivo. Our general hypothesis is that this form of mitochondrial dysfunction plays a critical role in the outcome of ischemic insults to the kidney and that its amelioration will beneficially impact on cell and tissue recovery from these insults. To test this hypothesis and further investigate its implications for understanding and treating ischemic acute renal failure we propose studies to: 1) Characterize the energetic deficit as it evolves during extended durations of hypoxia/reoxygenation and the effects of protective substrates to ameliorate it under those conditions. 2) Better define the mechanisms for the mitochondrial inner membrane abnormalities during the insult and their relative contributions to the energetic deficit. 3) Assess expression of the lesion and test efficacy of protective metabolites during ischemia/reperfusion of the kidney in vivo.

最近，由于对线粒体通透性转变机制的新见解以及对线粒体细胞色素 c 释放在细胞凋亡中的作用的认识，人们对线粒体功能障碍作为多种形式细胞损伤的介导者重新产生了兴趣。 近端肾小管是缺血性和中毒性急性肾功能衰竭期间的主要损伤部位，近端小管中的 ATP 产生对线粒体功能障碍特别敏感，因为根据不同的节段，体内近端小管细胞中糖酵解不存在或很少。 在本资助期间的研究中，我们发现了一种线粒体损伤，其特征是复合物 I 中的电子传递受到抑制，与基质凝结和部分断电相关，是新鲜分离的兔近端小管缺氧/​​复氧期间线粒体损伤的一种功能上重要的形式，在整体细胞恢复中发挥着关键作用。 病变：a)先于线粒体通透性转变和细胞色素c释放； b) 持续抑制原本存活的肾小管的能量功能； c) 非常容易被特定的柠檬酸循环代谢物所预防和逆转，这些代谢物促进线粒体内 ATP 产生和电子传输的无氧途径，或者在有氧条件下绕过复合物 I 阻断。 线粒体损伤在经受缺氧/复氧的新鲜分离的小管中表达，并且基于体内缺血/再灌注期间柠檬酸循环代谢物的超微结构变化和修饰。 我们的一般假设是，这种形式的线粒体功能障碍在肾脏缺血性损伤的结果中起着关键作用，其改善将有益于细胞和组织从这些损伤中恢复。 为了检验这一假设并进一步研究其对理解和治疗缺血性急性肾衰竭的影响，我们建议进行以下研究：1）表征在长时间缺氧/复氧过程中能量缺乏的演变，以及在这些条件下保护性底物改善能量缺乏的作用。 2）更好地定义损伤过程中线粒体内膜异常的机制及其对能量不足的相对贡献。 3) 评估病变的表达并测试体内肾脏缺血/再灌注期间保护性代谢物的功效。