Renal tubular cell injury is a critical component of the syndrome of acute renal failure secondary to ischemia and nephrotoxins. The past several years have seen progress in understanding the cellular pathophysiology of such injury but major fundamental issues remain to be resolved and a variety of maneuvers with potential for ameliorating such injury need to have their effiacy and mechanisms of action clarified. This has been extremely difficult with in vivo studies because of the complex interplay of factors occurring in the intact kidney which are not subject to direct measurement or experimental manipulation. Studies with isolated subcellular organelles have been valuable but are necessarily done outside of the integrated cellular milieu in which they actually function. The P.I. has refined a preparation of isolated renal tubules in suspension, enriched in proximal segments, which is suitable for critical direct study, under well controlled in vitro conditions, of major processes in the cellular pathophysiology of renal tubular cell injury including energy and adenine nucleotide metabolism, cellular monovalent cation and Ca++ homeostasis, and alterations in cell lipid and phospholipid metabolism. Preliminary studies on the course of changes in these parameters in a model of ischemic injury established with the preparation will be extended and models for study of nephrotic injury will be developed. Preliminary studies have evaluated the potential for a number of agents including phospholipase inhibitors, Ca++ channel blockers, fatty acid free albumin, impermeant solutes and exogenous adenine nucleotide addition to alter the course of ischemic injury in this model with the finding of significant beneficial effects for several of these maneuvers. These studies will be extended to better clarify which agents are effective and optimal conditions for their use and to gain insights into the mechanisms of their action. Additional proposed studies will utilize a model refined by the P.I. of Ca++ mediated injury to the inner mitochondrial membrane to better probe the nature of the process at this important intracellular site. The studies in this proposal will, thus, provide new insight into both mechanisms of renal tubular cell injury and efficacy and mechanisms of action of maneuvers for ameliorating such injury and the associated acute renal failure.
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