Work proposed for the next three years represents a continuation and expansion of ongoing experiments on the action of heavy metals on the rabbit kidney. The heavy metals of interest include Cd and Hg, and are of importance both because of problems of environmental pollution, and because of their well-known nephrotoxicity. However, the nature of the functional lesion in animals or man exposed to these metals is not yet clearly delineated. The proposal therefore specifically focuses on the lesion leading to aminoaciduria, i.e. the inhibition of amino acid reabsorption in the proximal tubule. Results so far show that this inhibition resembles what in a simpler system may be referred to as uncompetitive inhibition. The significance of the concept of uncompetitiveness, in a system as complex as the renal tubule, will be further investigated. The studies will utilize a new experimental approach which permits analysis of saturation and inhibition kinetics of amino acid transport without the complicating factors of long equilibrating infusions and at times very high peripheral plasma levels of amino acids, with consequent likelihood of metabolic breakdown of the infused compound and formation of potential competitive inhibitors. It is also necessary to distinguish between direct effects of the metals on amino acid carrier systems, and an indirect action of the inhibitors, mediated perhaps by more general cytotoxic effects. The final outcome of the work should be a better understanding of the action of the heavy metals on renal function.
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