CELLULAR PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE

这个项目的总体目标一直是改进 对肾脏细胞病理生理学的认识 急性缺血性损伤时近端小管细胞的损伤 肾功能衰竭。近端小管的悬浮液是由 胶原酶处理兔肾脏及其代谢 特征，特别是呼吸作用，细胞阳离子平衡 和细胞腺嘌呤核苷酸动态平衡，在 缺氧性损伤现在已经有了很好的定义。我们 我发现有几个动作显著改变了敏感度 对缺氧所致的损伤有保护作用。 它们是：以高密度孵化小管，降低细胞的pH值 在7.4~7.0或更低的培养基中，处理 含有高浓度外源性腺嘌呤核苷酸的小管 并用甘氨酸或谷氨酰胺处理肾小管。进一步 描述了它们的特点和作用机制 效果可以提供工具，用于批判性地评估 许多可能的病理生理过程和亚细胞位置 损伤实际上在氧气的发病机制中很重要。 剥夺-诱导肾小管细胞损伤并有助于引导 大鼠肾小管细胞损伤改善方法的研究进展 活着。在下一个资金阶段，我们将集中我们的 在三个方面开展工作。1)有效的细胞保护作用 甘氨酸将被研究以更完整地定义氧 甘氨酸被剥夺和复氧的条件 保护，甘氨酸活动的小管细胞内的位置， 其对离体肾小管保护作用的特异性 制备与缺氧性损伤及 甘氨酸代谢途径起到保护作用。2) 我们将扩大对高剂量防护作用的研究。 以阐明外源核苷酸的相对程度 由不同的嘌呤提供的保护。3)我们将分析 直接测定土壤pH值对降低土壤pH值的主要保护作用 胞液pH与培养液和细菌的独立调控 胞浆pH。多个进程在快速 缺氧性脑损伤发展过程中的时间框架 肾小管细胞损伤使得能够直接评估 如果对病理生理学的可靠见解是 将会被获得。这项建议中的研究提供了一个既定的 和多才多艺的方法来实现这一点。

The general aims of this project have been to improve understanding of the cellular pathophysiology of the renal proximal tubule cell injury which occurs during ischemic acute renal failure. Suspensions of proximal tubules are prepared by collagenase treatment of rabbit kidneys and their metabolic characteristics, particularly respiration, cell cation homeostasis and cell adenine nucleotide homeostasis, are studied in models of oxygen deprivation injury which have now been well defined. We have found that several maneuvers strikingly alter the sensitivity of the isolated tubules to oxygen deprivation-induced injury. These are: incubating tubules at high density, lowering the pH of the incubation medium from 7.4 to 7.0 or less, treating the tubules with high concentrations of exogenous adenine nucleotides and treating the tubules with glycine or gluthatione. Further delineation of the characteristics and mechanisms of these effects can provide the tools for critically assessing which of many possible pathophysiologic processes and subcellular sites of damage are actually important in the pathogenesis of oxygen deprivation-induces tubule cell injury and can help guide the development of methods for ameliorating tubule cell injury in vivo. During the next period of funding we will concentrate our work on three areas. 1) The potent, cytoprotective effects of glycine will be studied to more completely define the oxygen deprivation and reoxygenation conditions under which glycine is protective, the sites within the tubule cell of glycine's activity, the specificity of its protective effects for the isolated tubule preparation and oxygen deprivation-induced injury and the pathways of glycine metabolism which account for protection. 2) We will extend our studies of the protective effects of high doses of exogenous nucleotides to clarify the relative degrees of protection provided by different purines. 3) We will analyze the major protective effect of reducing pH by direct measurements of cytosolic pH and independent manipulations of medium and cytosolic pH. The interplay of multiple processes over a rapid time fram during the development of oxygen deprivation-induced tubule cell injury makes it important to be able to directly assess and manipulate them if reliable insights into pathophysiology are to be obtained. The studies in this proposal provide an established and versatile approach for achieving this.