Certain environmental toxins, chemicals of agricultural importance, as well as, drugs and industrial chemicals are capable of inducing dose dependent renal necrosis that is primarily confined to the proximal portion of the nephron. Our objectives are twofold: First, we plan to delineate, quantitatively and simultaneously, the acute chemical-induced changes in renal function and renal morphology with the goal of determining what parameters are the most sensitive indicators of early chemical induced proximal tubular necrosis. Second, we plan to delineate the mechanism by which certain environmental toxins, drugs, and other cited chemicals induce specific proximal tubular necrosis. This will be attempted by coupling three approaches: (1) We have designed, and plan to synthesize, closely related non-alkylating derivatives of various proximal tubular toxins for the purpose of evaluating their nephrotoxicity. (2) We plan to determine if the intrarenal distribution of certain radiolabelled proximal tubular toxins is confined only to proximal tubular cells, and if they are bound to renal tissue in an irreversible fashion. (3) Attempts will be made to modify or obliterate the necrosis induced by certain proximal tubular toxins by pretreatment with compounds that alter the proximal tubular transport of anions or cations (i.e., probenecid) or act as scavengers of alkylating agents (i.e., thiols).
