Research proposed in this application is designed to improve our understanding of the nephrotoxicity of heavy metals, with special emphasis on the action of Cd. Two primary objectives have been defined: 1) Does Cd uptake by the kidney following acute administration of diffusible complexes such as Cd-mercaptoethanol resemble that described in some detail for the transfer of Cd from the intestinal lumen into the mucosa. Confirmation will be sought of preliminary results showing that both processes are diffusion- limited, so that prolonging the renal residence time of Cd injected in an arterial bolus will increase its extraction from blood. The A - V transit time will be prolonged by aortic occlusion short enough to avoid anoxic damage. The ability of EDTA to extract the freshly accumulated Cd from the kidney will be used as measure of internalization of the metal. Also, the sensitivity of the diffusion-limited uptake to polyvalent cations will be determined; all these factors are characteristic of jejunal Cd transport. The second major aim is to ascertain whether Cd freshly accumulated in the kidney during aortic occlusion will depress amino acid transport as much immediately as some 2 days after exposure. Results of these studies will have an important bearing on the concept of critical Cd levels in the renal cortex. Additional questions to be investigated include 1) Are effects of metals on amino acid reabsorption related to their interfering with previously observed in the rat of appearance in renal venous blood of isotope from an acid labelled at various sites; the question is whether Cd alters the pattern of these differences. 2) To what extent do effects of metals reflect circulatory rather than cytotoxic factors? This will be studied by altering renal blood flow by extrarenal maneuvers such as aortic constriction. 3) Is the action of Cd similar to that of Hg, Ni And other nephrotoxic compounds?
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