By interfering with renal growth and development, congenital urinary tract obstruction constitutes on of the most important causes of renal failure in infants and children. Obstructive nephropathy is also a significant cause of renal insufficiency in the adult. The central hypothesis to be tested in this proposal is that chronic unilateral ureteral obstruction (UUO) induces phenotypic transformation in renal tubular epithelial (RTE) cells that leads to the development of tubular atrophy and interstitial fibrosis. The phenotypic changes include altered expression of growth factors, loss of polarity, expression of mesenchymal markers, and detachment from the basement membrane. Apoptosis of RTE cells is markedly increased contributing to tubular atrophy, while interstitial fibroblasts undergo proliferation and myofibroblast transformation, leading to progressive interstitial fibrosis. The secondary hypothesis is that these events are modulated by the developmental stage of the kidney at the time of obstruction. In the proposed research plan, mRNA quantitation, in situ hybridization, and immonohistochemical techniques will be used to investigate the renal cellular response to UUO (and its release) in the neonatal and adult rat. To control for internephron heterogeneity, single nephrons will also be obstructed by micropuncture. RTE cell microfilament and growth factor production will be measured, and epidermal growth factor (EGF) and integrin receptor distribution will be determined. Components of extracellular matrix and mediators of interstitial fibrosis will also be examined. Factors regulating the RTE cell phenotype and apoptosis will be studied, including the response to exogenous EGF, insulin-like growth factor-1, retinoic acid, and antioxidant agents: these compounds are likely to reduce renal injury and accelerate recovery. By elucidating the mechanisms by which the RTE cell regulates the responses to UUO, the proposed studies may lead to new interventions to avert progression of renal insufficiency in patients with obstructive nephropathy.
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