The long-term goal of this project is to identify pharmacological treatments for acute organ failure. Cell injury and death induced by oxidative stress occur during ischemia/reperfusion (I/R), leading to failure of different organs such as the heart, brain, liver, and kidneys. Furthermore, oxidative stress is often the mediator of drug-, toxicant-, and trauma-induced mitochondrial dysfunction and cell death. Mitochondrial dysfunction and associated ATP depletion leads to cell injury and death. Unfortunately, there are no truly effective therapies that can promote cell and organ repair/regeneration, and the return of organ function after injury has occurred. Cells replace old and dysfunctional mitochondria through mitochondrial biogenesis. Peroxisome proliferator-activated receptor gamma coactivator-11 (PGC-11) is generally thought to be the master regulator of mitochondrial biogenesis in adipose tissue, heart, and liver, and we have shown that PGC-11 mediates mitochondrial biogenesis in renal proximal tubular cells (RPTC). Furthermore, we showed that over- expression of PGC-11 increases mitochondrial biogenesis in RPTC after oxidant injury and accelerated recovery of cellular functions. These exciting results support the hypothesis that post-injury mitochondrial biogenesis may be efficacious in stimulating cell and organ repair/regeneration. Our preliminary data revealed that administration of a flavanoid increases PGC-11 levels and produces mitochondrial biogenesis in control RPTC and in the mouse kidney. The preliminary data support our hypotheses that PGC-11 is a key mediator of mitochondrial biogenesis and cell regeneration after oxidant and I/R injury, and flavanoid-induced mitochondrial biogenesis will promote regeneration of RPTC and kidney function after injury. The following Specific Aims will test these hypotheses: 1) Elucidate the mechanisms of PGC-11 regulation after oxidant injury in RPTC. 2) Determine the mechanism flavanoid-induced mitochondrial biogenesis in RPTC. 3) Determine the effect of flavanoid-induced mitochondrial biogenesis on mitochondrial function, and cell death and regeneration before and after oxidant injury in RPTC. 4) Determine the effect of a flavanoid on mitochondrial biogenesis and the acceleration of recovery of renal function after I/R injury. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic situations. Acute renal failure remains an enormous public health concern as no truly effective therapies have proven to be useful after renal injury. Mitochondrial biogenesis, the process of replacing dysfunctional mitochondria, presents a novel avenue for stimulating cell and organ repair/regeneration after renal injury, promoting the return of renal function. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic situations. ? ? ?
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