PATHOPHYSIOLOGY OF RENAL ISCHEMIA, ANOXIA, HYPOPERFUSION

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The pathophysiology of renal injury induced by three forms of oxygen deprivation ischemia, anoxia and hypoperfusion will be examined and contrasted. We will also study the effect of interventions designed to modify or prevent the biochemical consequences of oxygen deprivation. These interventions will elucidate the mechanisms that lead to cellular injury. They will also provide valuable information needed for the development of therapies aimed at preventing or ameliorating acute renal failure. Two in vitro models for these studies will be used: an isolated proximal tubular suspension and an isolated kidney preparation perfused by an erythrocyte enriched medium. The use of these in vitro models will allow the study of intrarenal mechanisms of ischemic and anoxic injury independent of extraneous influences such as blood pressure, sympathetic nerve activity and systemic hormones. Studies planned for the isolated tubules and isolated erythrocyte perfused kidney (IEPK) will complement each other. The isolated tubule studies will focus on the effect of various forms of oxygen deprivation on cellular transport processes as well as on the biochemical events that lead to cellular injury. On the other hand, the IEPK will allow the comparison of the effects of ischemia, anoxia and hypoperfusion on integrated organ function and on the segmental pattern of nephronal injury. These studies will determine whether the interventions that successfully modify the transport abnormalities and biochemical consequence of ischemia or anoxia in the tubular preparation, produce similar effects in the intact kidney and are translated into improvement in glomerular filtration rate, tubular sodium handling, and concentrating ability. Specifically the plan is to: (1) Examine the effects of ischemia and anoxia in both these models and of hypoperfusion in the IEPK. (2) Determine the role played by depletion of cellular energy stores on ischemic and anoxic damage. (3) Study the role played by the formation of oxygen free radicals in ischemic injury. (4) Investigate the importance of phospholipase activation following cellular injury in ischemia by examining the effects of agents that both stimulate and inhibit cellular phospholipase activity on ischemic injury. (5) Elucidate the role of alterations in cellular calcium in mediating injury following ischemia.