(Directly taken from the application) The overall objective of this grant is to examine the role of reactive oxygen intermediates (ROI), antioxidant mechanisms, and the cellular redox state in the pathogenesis of polycystic kidney disease (PKD) in Han:SPRD rats and to determine whether changes in the cellular redox state mediate the marked effects of acid or base administration on the development of renal cystic disease in this model. The general hypothesis is that the proliferation of tubular epithelial cells is controlled by the redox state, that the development of PKD is accompanied by abnormalities in redox metabolism, that experimental modifications of the redox state will alter the development of PKD, and that changes in the redox state mediate the marked effects of acid or base administration on cystogenesis. In previous studies we have demonstrated that metabolic factors modulate the development of PKD. While inhibition of the renin angiotensin system affords a moderate protection and high dietary sodium chloride causes a moderate aggravation, the administration of acid or alkali has dramatic effects on the development of PKD in Han:SPRD rats. Our hypothesis contends that the effects of these metabolic factors on the development of PKD are mediated by changes in the cellular redox state. In support of this hypothesis, preliminary studies have shown an aggravation of PKD in Han:SPRD rats by the administration of inhibitors of critical antioxidant enzymes (gamma-glutamyl cysteine synthetase or Cu-Zn superoxide dismutase) and an increased oxidation of nonfluorescent DCFH- DA to fluorescent DCF by LLC-PK1 cells following extracellular acidification. The proposed studies will determine: 1) whether the development of cystic disease in Han:SPRD rats is accompanied by changes in ROI generation, antioxidant enzymes, and redox state; 2) the effect of experimental conditions that alter the cellular redox state of tubular epithelial cells, such as oxidative stress induced by hydrogen peroxide, deficiency or excess of glutathione or alpha-tocopherol, inhibition of catalase, administration of microsomal cytochrome P450 inhibitors or inducers, administration of renal peroxisomal proliferators, and inhibition of the NADPH oxidase system on the development of PKD; 3) whether the effects of acidification or alkalinization on tubular epithelial cell proliferation in vitro and on renal cystogenesis in vivo are mediated by alterations in redox metabolism. Of all available animal models, the Han:SPRD rat is the one that best resembles human autosomal dominant polycystic kidney disease. In addition we have found that some of the factors that alter the development of PKD in Han:SPRD rats also affect cystogenesis in humans. Further identification and knowledge of environmental and metabolic factors that modulate the development of inherited renal cystic diseases are of great clinical relevance and together with the information gained from the identification of the responsible genes will likely contribute to a better understanding and ultimately a treatment for these diseases.
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