? Obstruction of the upper urinary tract is a major clinical problem in both children and adults that results in progressive and ultimately irreversible renal damage. The majority of obstructive renal injury is attributed to renal cell loss via apoptosis and to progressive renal fibrosis. A number of inflammatory mediators have been implicated in the pathophysiology of renal obstruction, including tumor necrosis factor (TNF). TNF is a known cytotoxic agent capable of inducing apoptotic renal cell death in ischemic models of renal injury. While increased expression of TNF has been demonstrated following renal obstruction, the role of TNF in obstruction-induced renal cell apoptosis and fibrosis has not been elucidated. Our long term objectives are therefore to identify TNF as an important mediator of apoptosis and renal fibrosis during obstruction, and further, to develop a clinically relevant therapeutic strategy that will limit or prevent TNF induced obstructive renal injury. These goals will be accomplished using a rat model of unilateral renal obstruction by 1) determining the time course of renal cell apoptosis and fibrosis during obstruction, 2) determining the role of TNF in obstruction-induced renal apoptosis and fibrosis using the specific TNF inhibitor, soluble TNF receptor I (RTBP1), and 3) investigating the mechanisms of obstruction-induced renal TNF expression.
For Specific Aim I, renal cortical tissue wilt be harvested following 1, 3, 7, or 14 days of obstruction, and assessed with regards to TNF expression and activity, TGF-beta expression, collagen deposition and fibrosis, and degree of apoptosis.
Specific Aim II will assess the impact of TNF inhibition on obstruction-induced renal injury by investigating the parameters outlined in Aim I using rats that have been exposed to RTBP1 during the period of obstruction.
Specific Aim III will assess the mechanisms of obstruction-induced renal TNF expression by investigating known regulators of TNF production, including nuclear factor kappaB and p38 mitogen activated protein kinase. Overall, the objective of this proposal is to apply and enhance the knowlegde gained by the applicant during her residency and fellowship training to develop a clinically relevant therapeutic approach to the treatment and prevention of obstructive renal injury ? ?
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