CELLULAR PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE

急性肾衰竭的细胞病理生理学

• 批准号: 3232605
• 负责人: JOEL M. WEINBERG
• 金额: $ 10.27万
• 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 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3232605
• 关键词: adenine nucleotides; aminoacid; bioenergetics; calcium metabolism; cellular pathology; disease /disorder model; electrolyte balance; growth media; histopathology; kidney metabolism; kidney pharmacology; lipid metabolism; lipid peroxides; mitochondrial membrane; nucleotide metabolism; perfusion; phospholipids; renal failure; renal ischemia /hypoxia; renal toxin; renal tubular transport; renal tubule; tissue /cell culture

Renal tubular cell injury is a critical component of the syndrome of acute renal failure secondary to ischemia and nephrotoxins. The past several years have seen progress in understanding the cellular pathophysiology of such injury but major fundamental issues remain to be resolved and a variety of maneuvers with potential for ameliorating such injury need to have their effiacy and mechanisms of action clarified. This has been extremely difficult with in vivo studies because of the complex interplay of factors occurring in the intact kidney which are not subject to direct measurement or experimental manipulation. Studies with isolated subcellular organelles have been valuable but are necessarily done outside of the integrated cellular milieu in which they actually function. The P.I. has refined a preparation of isolated renal tubules in suspension, enriched in proximal segments, which is suitable for critical direct study, under well controlled in vitro conditions, of major processes in the cellular pathophysiology of renal tubular cell injury including energy and adenine nucleotide metabolism, cellular monovalent cation and Ca++ homeostasis, and alterations in cell lipid and phospholipid metabolism. Preliminary studies on the course of changes in these parameters in a model of ischemic injury established with the preparation will be extended and models for study of nephrotic injury will be developed. Preliminary studies have evaluated the potential for a number of agents including phospholipase inhibitors, Ca++ channel blockers, fatty acid free albumin, impermeant solutes and exogenous adenine nucleotide addition to alter the course of ischemic injury in this model with the finding of significant beneficial effects for several of these maneuvers. These studies will be extended to better clarify which agents are effective and optimal conditions for their use and to gain insights into the mechanisms of their action. Additional proposed studies will utilize a model refined by the P.I. of Ca++ mediated injury to the inner mitochondrial membrane to better probe the nature of the process at this important intracellular site. The studies in this proposal will, thus, provide new insight into both mechanisms of renal tubular cell injury and efficacy and mechanisms of action of maneuvers for ameliorating such injury and the associated acute renal failure.

肾小管细胞损伤是急性肾综合征的重要组成部分， 继发于缺血和肾毒素的肾衰竭。 过去几 多年来，在理解细胞病理生理学方面取得了进展， 但一些重大的根本性问题仍有待解决， 有可能改善这种损伤的各种操作需要 明确其功效和作用机制。 这是 由于复杂的相互作用， 发生在完整肾脏中的因素，这些因素不受直接 测量或实验操作。 分离的研究 亚细胞器是有价值的，但必须在外部完成 它们在其中发挥作用的细胞环境。 的 P.I.已经改进了悬浮的分离肾小管的制备， 在近端节段中富集，这适合于关键的直接研究， 在良好控制的体外条件下， 肾小管细胞损伤的细胞病理生理学包括能量和 腺嘌呤核苷酸代谢、细胞单价阳离子和Ca++ 内稳态以及细胞脂质和磷脂代谢的改变。 对模型中这些参数变化过程的初步研究 缺血性损伤的建立与准备将延长， 将开发用于研究肾病损伤的模型。 初步 研究已经评估了许多药剂的潜力，包括 磷脂酶抑制剂，Ca++通道阻断剂，无脂肪酸白蛋白， 不渗透的溶质和外源腺嘌呤核苷酸的添加，以改变 在该模型中缺血性损伤的过程中， 其中几种操作的有益效果。 这些研究报告将 扩展以更好地阐明哪些代理是有效和最佳的 的使用条件，并深入了解其 行动上 其他拟议的研究将利用一个模型， P.I. Ca++介导的线粒体内膜损伤， 探索这个重要的细胞内位点的过程的本质。 的 因此，本提案中的研究将为这两方面提供新的见解。 肾小管细胞损伤的机制以及 演习的作用，以改善这种伤害和相关的急性 肾衰竭