We have developed a body of evidence relating certain forms of ischemic and toxic acute renal failure to the special susceptibility of cells lining the medullary thick ascending limb to hypoxic injury. A key characteristic of such injury is its modification by active transport and its apparent dependence on mitochondrial electron flow rather than cellular levels of ATP. We now propose to explore the mechanisms responsible for the notorious susceptibility of diabetic patients to ischemic medullary injury and to radiocontrast nephropathy. Particular attention will be paid to the role of free radical formation in causing the renal lesions of hypoxia seen in the medullary thick limb. In addition, experimental models of contrast nephropathy in rats, with which we have had some experience, will be utilized to gain insight into the ways in which diabetes mellitus might predispose patients to this form of renal injury. We intend to seek answers to the following related questions. Are the lesions of anoxia observed in the thick limb caused entirely or in part by free radicals formed in greater abundance when transport work is increased in the presence of hypoxia? If so, what is the nature of the free radical species formed and what are the implications for prevention or treatment? Is experimental diabetes mellitus associated with enhanced susceptibility to hypoxic renal injury or to radiocontrast injury as seen in the isolated perfused kidney model as well as in intact rats? If diabetes can be shown to predispose to medullary injury, what is the mechanism of its effect? Are autocrine or paracrine substances that modulate metabolism, normally formed by medullary cells, produced less readily in diabetes? Do radiocontrast agents have metabolic effects in the medulla of diabetic kidneys that differ from their effects in kidneys of normal subjects.? The biological systems employes will include intact rats, isolated perfused rat kidneys, and separated medullary thick ascending limb cells derived from enzymatic digestion of rabbit and rat kidneys.

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