Unilateral ureteral obstruction [UUO] with subsequent hydronephrosis is a common clinical occurrence. It affects both men and women and occurs in approximately 1 percent of the pediatric population. Prominent changes in UUO include decreases in renal blood flow [RBF] and glomerular filtraion rate [GFR], increased fibrosis and apoptosis. Transforming Growth Factor- beta [TGF-beta] is increased in UUO. TGF-beta is pro-fibrotic, and it can be either pro-apoptatic or anti-apoptatic. Nitric oxide [NO], synthesized from arginine by NO Synthase [NOS], can either promote or attenuate both fibrosis and apoptosis. In preliminary data presented herein, we have found that pre- treatment of rats with UUO with an antibody to TGF-beta [1D11] is associated with decreased renal apoptosis and fibrosis; conversely, mice with a targeted deletion of the inducible form of NOS [iNOS] exhibit increased renal apoptosis and fibrosis with UUO. We further demonstrate that UUO of 24 hours duration is associated with decreases in both RBF and GFR of greater than 90 percent, and that we can surgically reverse the obstruction with a concomitant improvement in renal function. We propose that treatments which either decrease renal TGF-beta or increase renal NO will result in amelioration of apoptotic and fibrotic processes in UUO. It is the hypothesis of this proposal that decreasing apoptotic and fibrotic processes in the obstructed kidney will lead to amelioration of the decrements in renal function associated with UUO. To validate this hypothesis, we will do the following: 1)Assess the effect of an antibody to TGF- beta [1D11] on renal function and histopathology in UUO 2)Assess the effect of increased renal NO [by providing arginine or transducing NOS] on renal function and histopathology in UUO 3)Determine if targeting apoptosis affects renal fibrosis and function in UUO 4)Determine the temporal sequence of renal functional and histopathological changes in UUO and the reversibility of these changes. Results of these experiments should demonstrate how the cytokines TGF-beta and NO contribute to fibrotic and apoptotic processes and renal functional changes of UUO. These results should provide the basis for future clinical studies in ameliorating renal dysfunction in patients with UUO.
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