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).
|Krejci, M E; Bretz, N S; Koechel, D A (1996) Citrinin produces acute adverse changes in renal function and ultrastructure in pentobarbital-anesthetized dogs without concomitant reductions in [potassium]plasma. Toxicology 106:167-77|
|Koechel, D A; Krejci, M E; Bretz, N S (1995) 4-Maleimidohippuric acid--a tailor-made, direct, site-specific nephrotoxin: effects on renal function and ultrastructure in pentobarbital-anesthetized dogs. Toxicology 96:115-26|
|Koechel, D A; Krejci, M E (1993) Extrarenal and direct renal actions of atractyloside contribute to its acute nephrotoxicity in pentobarbital-anesthetized dogs. Toxicology 79:45-66|
|Ridgewell, R E; Krejci, M E; Koechel, D A (1992) Acute effects of a gamma-glutamylated derivative of S-(1,2-dichlorovinyl)-L-cysteine on renal function and ultrastructure in pentobarbital-anesthetized dogs: site-specific toxicity involving S1 and S2 cells of the proximal tubule. Am J Vet Res 53:840-6|
|Krejci, M E; Koechel, D A (1992) Acute effects of carboxyatractyloside and stevioside, inhibitors of mitochondrial ADP/ATP translocation, on renal function and ultrastructure in pentobarbital-anesthetized dogs. Toxicology 72:299-313|
|Koechel, D A; Krejci, M E; Ridgewell, R E (1991) The acute effects of S-(1,2-dichlorovinyl)-L-cysteine and related chemicals on renal function and ultrastructure in the pentobarbital-anesthetized dog: structure-activity relationships, biotransformation, and unique site-specific nephrotoxicity. Fundam Appl Toxicol 17:17-33|
|Krejci, M E; Ridgewell, R E; Koechel, D A (1991) Acute effects of the D-isomer of S-(1,2-dichlorovinyl)cysteine on renal function and ultrastructure in the pentobarbital-anesthetized dog: site-specific toxicity involving the S1 and S2 cells of the proximal tubule. Toxicology 69:151-64|