TGF BETA EXPRESSION FOLLOWING ISCHEMIC ACUTE RENAL FAIL

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Acute renal failure is a major clinical complication associated with approximately 50 percent mortality. Currently there are no established therapies for this disorder beyond supportive care and dialysis. Transforming growth factor beta (TGF-beta) is a polypeptide growth factor thought to contribute to renal fibrosis. However, its extracellular matrix promoting properties may serve an important functional role in the kidney in the setting of acute renal failure. This proposal is directed toward elucidating the influence of transforming growth factor-beta (TGF-beta) plays during renal repair acute renal ischemia. It hypothesized that TGF-beta activity plays an important role in the structural and functional recovery of the kidney post-ischemic injury. Several recent studies have shaped the current proposal. Among them is 1) the observation that TGF-beta1 mRNA and peptide are expressed in regenerating proximal tubules post-ischemia in the rat. 2). The observation that extracellullar matrix (ECM) genes associated with tissue remodeling are expressed in a manner consistent with TGF-beta activity. 3) The observation that the expression of these ECM gene products are significantly attenuated with a neutralizing antibody to TGF-beta post-ischemia. The first set of goals are aimed at identifying and characterizing TGF-beta activity in vivo in response to renal injury. In specific aim number 1, TGF-beta signaling receptors will be identified, localized and their activity measured in response to renal injury. Specific aim number 2 will determine the potential beneficial effects of TGF-beta1 peptide on renal repair post-ischemic injury in rats. In specific aim number 3, we will determine if the loss of the TGF-beta1 gene affects the post-ischemic repair process in TGF-beta1 -/- mice. In specific aims number 2 and number 3 we will analyze repair by measuring renal function, analyzing renal morphology and measuring the expression of genes associated with tissue repair. A second set of goals is aimed at understanding the mechanism of the renal response to injury. In specific aim number 4 we will determine if TGF-beta activity post-ischemic injury is enhanced via RNA transcriptional mechanisms. In specific aim number 5, we will identify potentially relevant cis-acting elements of the 5' proximal promoter region of the TGF-beta1 gene that demonstrate altered transcriptional factor binding activity post-ischemic injury by DNAse I footprinting and gel-shift analysis. These experiments will provide important data concerning the role of a highly expressed growth factor in a model of renal injury and provide new insight into the possible mechanism by which the kidney repairs itself following ischemic injury.