MECHANISMS OF RENAL ADAPTATION TO ANOXIA

$185,205P01FY2001HDNIH

Yale University, New Haven CT

Investigators

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Abstract

The overall objective of this PPG is to advance our understanding of the cellular adaption to oxygen deprivation. The kidney offers a unique opportunity to investigate fundamental mechanisms which respond to limitation in oxygen. The impact of renal development on cellular respiration and susceptibility to oxygen deprivation is the primary focus of our proposed studies. It is often stated that the young kidney is more resistant to the development of acute failure that the adult kidney. However, the mechanism of tolerance have not been investigated formally. To study this problem, we propose: a) To determine the metabolic factors which contribute to the tolerance of the developing tubule to anoxia. This will entail studies of cellular energy distribution between transport and non-transport functions; the glycolytic pathway, as well as intracellular pH in the tolerance of the immature tubules. b) To evaluate polarity and cytoskeletal changes during development and after anoxia by determining the alterations in intracellular localization of Na/K-ATPase subunits, and fodrin. c) To define the adaptive response to anoxia by investigating the expression and localization of heat shock proteins during and following anoia. To accomplish these specific aims we will use an integrated approach to study the mechanisms of tolerance of the immature tubules to anoxia. Studies will utilize a suspension of tubules obtained after collagenase digestion from immature rats (age 8-10 days old) and mature rate (8-10 weeks old). Techniques that will be used include measurement of O2 consumption rates during reperfusion, Northern and Western analysis, gel retardation assay and immunocytochemical localization. Based on these proposed studies, new information concerning the structural and functional adaptation to oxygen deprivation will be defined and the basic mechanisms involved will be relevant to an understanding of adaptive processes in renal epithelial cells and other organs.

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