Ischemia/reperfusion and cisplatin-induced acute renal failure are associated with rapid duration dependent decreases in cellular fatty acid oxidation (FAO). Inhibition of FAO eventually leading to mitochondrial dysfunction represents an important mechanism causing proximal tubule cell death. Our hypothesis is that inhibition of PPARa activation and coactivator PGC-1 result in interrelated and/or independent effects on fatty acid oxidation and mitochondrial function which play an important role in the renal tubular epithelial cell injury induced by cisplatin. Our first specific aim will examine the role of PPARa, activation in cisplatin induced proximal tubule cell injury. lA.i) We will examine the time course and dose dependent effect of cisplatin on cell death, caspase activation, endonuclease activation in tubules prepared from PPARa wild type and null mice. ii) We will examine the time course and dose dependent effect of cisplatin, and the effects of PPARa ligands on caspase and endonuclease activation in mouse proximal tubular cells in culture (TKPTS). 1B.i) We will examine the time course and intracellular concentrations of FAO metabolite palmitoylcarnitine accumulated during cisplatin injury. ii) We will examine the effect of palmitoylcarnitine on cytochrome C release, mitochondria permeability transition, caspase, and endonuclease activation and cell death. 1C.i) We will examine the time course and dose dependent effect of cisplatin on mitochondrial function in tubules prepared from PPARa wild type and null mice. ii) We will examine the time course and dose dependent effect of cisplatin, and the effects of PPARa ligands on mitochondrial function in proximal tubular cells (TKPTS). 1D. We will examine the effects of cisplatin on renal function and histology, caspase activation, endonuclease activation in PPARa wild type and the null mice and to examine the effects of PPARa ligands administered to these mice on the same end points.
In Specific Aim 2, we will examine the role of proximal tubule coactivator PGC-1 in cisplatin-induced injury. 2a) We will examine the effects of cisplatin on the expression of coactivator PGC-1 in mouse proximal tubules, and determine its nephronal distribution. 2b) We will examine the effect of forced expression of PGC-1 on cisplatin-induced inhibition of PPARa activity, FAO and mitochondrial functional capacity. 2c) We will determine if PPARa ligands modify cisplatin-induced inhibition of PGC-1. These studies should help establish the pathophysiologic role of PPARa and PGC-1 in cisplatin induced inhibition of FAO and mitochondrial dysfunction and also should help elucidate whether PGC-1/PPARa regulatory pathway is a candidate target for the investigation of novel therapeutic strategies aimed at the amelioration of energy metabolic dysfunction in various forms of acute renal failure.
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