DRUG-INDUCED NEPHROTOXICITY: A CELL CULTURE APPROACH

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The long-term objective of the proposed research plan is the formation of an in vitro cell culture model system for the study of aminoglycoside-induced nephrotoxicity. The foundation for this model system rests on a newly established cell culture of the human renal proximal convoluted tubule. Preliminary data has clearly shown that these cells respond to aminoglycoside exposure by formation of lysosomal myeloid bodies. The specific aims of the proposed research is initially to reinforce preliminary findings suggesting that aminoglycoside toxicity and myeloid body formation do not correlate directly. Rather, it appears that the least toxic aminoglycosides are the most efficient at inducing myeloid body formation. Additional specific aims center on an overall assessment of lysosomal function and ion transport alterations elicited by exposure to the aminoglycosides. The above parameters will be further perturbed to enhance and/or correct these alterations by changing the cation composition of the serum-free growth medium in which these cells grow. An understanding of the mechanism of aminoglycoside-induced nephrotoxicity may lead to clinical improvements in hospitalized patients suffering from sepsis.