APOPTOSIS IN TUBULAR ATROPHY OF PROGRESSIVE RENAL FAILURE

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Chronic renal failure is initiated primarily by glomerular injury, but tubular atrophy is a better predictor of renal disease progression, despite its prognostic importance, tubular atrophy is only a description for the absence of renal tubular epithelial cells (RTC) and the molecular mechanisms underlying RTC deletion are unknown. Based upon preliminary data which demonstrates that Fas expression is increased in RTC in chronic renal failure, the overall goal of this proposal is to determine whether hypoxia induces Fas-dependent RTC apoptosis. The hypothesis which will guide these experiments is that in chronic renal failure, hypoxia promotes RTC apoptosis through induction of RTC Fas expression. Furthermore, ligation of RTC Fas ligand with up-regulated Fas on adjacent target RTC induces lymphocyte-independent, fratricidal apoptosis via activation on signaling pathways that include down-regulation of bcl-2 and/or stimulation of bcl-2 phosphorylation. The goals of this project will be approached with the following specific aims: 1. To test whether hypoxia promotes RTC apoptosis through Fas induction, the effects of hypoxia on Fas function and apoptosis will be investigated. 2. To test for Fas-dependent fratricidal apoptosis, the RTC Fas-RTC Fas ligand interaction will be characterized. 3. To test whether Fas induction contributes to the chronic renal disease phenotype, in vivo and in vitro studies will be conducted to inhibit Fas activation. Upon completion of the proposed studies, we expect to provide a better understanding of the mechanisms which regulate tubular atrophy, thereby forming a basis for the design of therapeutic strategies to inhibit tubular atrophy and the progression of chronic renal disease.