PATHOGENESIS OF ISCHEMIC RENAL DISEASE

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Although cellular energy depletion is a hallmark of transient tissue ischemia, the pathogenic mechanism(s) that initial cell injury remain unknown. A host of studies in disparate models and tissues have suggested a number of potentially pathogenic mechanisms that could account for ischemic cell injury. One scheme that could unify these observations and serves as the central theme of this proposal, is that severe adenine nucleotide (ATP) depletion precipitates prolonged elevation of cytosolic Ca2+ (Cai). The prolonged increase in Cai is thought to activate critical Ca-dependent enzymes such as cell phospholipases and/or proteases that catalyze rapid degradation of plasma and organelle membranes with the subsequent release and accumulation of toxic lipid metabolites. Result and membrane breakdown and/or the detergent properties of free fatty acids could permit further increases in cell Cai. In addition, Ca-activated processes could disrupt cytoskeletal structures required for maintenance of cell function and directly injure mitochondria. Furthermore, loss of small cell proteins such as kidney fatty acid binding proteins, capable of buffering the rise in toxic, free fatty acids, could exacerbate this cycle. Finally, the combined insult of loss of cytoskeletal structures, unbound fatty acids and cell Cai could fuel irreversible membrane breakdown. This proposal will examine each of these potential pathogenic factors and their relationship to changes in cell Cai. We will also probe the mechanism of several potentially protective maneuvers such as the imposition of extracellular acidosis or the induction of heat shock proteins as a means to further identify important biochemical events that are the basis of ischemic cell injury. In these studies three different in vitro models will be utilized: primary cultures of mouse proximal tubule cells; suspensions of rat proximal tubules and the isolated erythrocyte perfused kidney. Each of these models provide unique and complementary advantages for the purposes of addressing these issues.