GLUTATHIONE AND MITOCHONDRIA IN TOXIC RENAL INJURY

谷胱甘肽和线粒体功能在免疫中发挥重要作用 保护细胞免受损伤和维持细胞 体内平衡 肾脏容易受到许多有毒物质的伤害。 化学物质和病理状态。 肾单位的所有部分， 然而，它们对损伤并不同样敏感。 校长 本研究的目的是描述处置和 谷胱甘肽在肾脏线粒体中的作用，并研究其在肾脏线粒体中的作用。 肾脏谷胱甘肽状态和线粒体功能影响 损伤 分离的线粒体和纯化或高度富集的细胞 来自雄性Fischer的肾单位的单个片段的悬浮液 将使用344只大鼠。 因为他们的优势， 因此，易于隔离，将进行初步研究 近端肾小管细胞和肾皮质线粒体。 的 具体的问题是：1）肾的起源是什么？ 线粒体谷胱甘肽和它的处置如何调节？ 2)谷胱甘肽在肾近端肾小管上皮细胞中的作用 线粒体功能 3)谷胱甘肽状态和 线粒体在肾近端癌易感性中的作用 肾小管细胞化学损伤？ 4)能否制定程序 为了分离出高度富集的粗上升分支种群， 远端肾小管和皮质集合管细胞，以及如何 它们的生化特性和对损伤的敏感性 与近端肾小管细胞的相似吗 Percoll密度梯度 离心将用于细胞纯化。 毛地黄皂苷 分离的细胞的分级分离将用于分离胞质溶胶 和线粒体，使更直接的研究线粒体 功能 选择性改变谷胱甘肽浓度的药物 和氧化还原状态以及那些改变线粒体生物能量学的 将探讨谷胱甘肽在 线粒体功能 使用会导致化学伤害 各种有毒化学物质，以及谷胱甘肽和 线粒体氧化活性在保护和敏感性 伤害将是氢过氧化物，甲基乙烯基酮，S-（2- 氯乙基）-DL-半胱氨酸）和需要代谢的化合物 激活（止痛剂对乙酰氨基酚，抗生素 头孢啶，细胞对损伤敏感性的基础状态 也将被调查。 这项研究将有助于提供更好的 了解肾脏药物代谢和生化 化学物质产生肾毒性的机制。

Glutathione and mitochondrial functions play important roles in protecting cells from injury and in maintenance of cellular homeostasis. The kidneys are susceptible to injury from many toxic chemicals and pathological states. All segments of the nephron, however, are not equally sensitive to injury. The principal objective of this research is to characterize the disposition and role of glutathione in renal mitochondrial and to study the influence of glutathione status and mitochondrial function in renal injury. Isolated mitochondria and purified or highly enriched cell suspensions of individual segments of the nephron from male Fischer 344 rats will be used. Because of their predominance and, therefore, ease of isolation, initial studies will be conducted with proximal tubular cells and renal cortical mitochondria. The specific questions addressed are: 1) What is the origin of renal mitochondrial glutathione and how is its disposition regulated? 2) What is the role of glutathione in renal proximal tubular mitochondrial function? 3) What role do glutathione status and mitochondrial function play in the susceptibility of renal proximal tubular cells to chemical injury? 4) Can procedures be developed to isolate highly enriched populations of thick ascending limb, distal tubular, and cortical collecting tubular cells, and how do their biochemical properties and susceptibility to injury compare to those of proximal tubular cells? Percoll density-gradient centrifugation will be used in cell purification. Digitonin fractionation of isolated cells will be used to separate cytosol and mitochondria, enabling more direct study of mitochondrial function. Agents that selectively alter glutathione concentrations and redox status and those that alter mitochondrial bioenergetics will be employed to explore the role of glutathione in mitochondrial function. Chemical injury will be induced by the use of various toxic chemicals, and the role of glutathione and mitochondrial oxidative activity in protection from and sensitivity to injury will be hydroperoxide, methyl vinyl ketone, S-(2- chloroethyl)-DL-cysteine) and compounds requiring metabolic activation (the analgesic acetaminophen, the antibiotic cephaloridine, the base status on cellular susceptibility to injury will also be investigated. The research will help provide a better understanding of renal drug metabolism and the biochemical mechanisms by which chemicals produce nephrotoxicity.