TGF-beta superfamily in neonatal obstructive nephropathy and recovery

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DESCRIPTION (provided by applicant): Congenital obstructive nephropathy is the most important identifiable cause of renal impairment in infants and children. Despite this, indications for surgical intervention are controversial, and renal recovery is often disappointing. While mechanisms responsible for renal injury resulting from urinary tract obstruction are elucidated in models of complete unilateral ureteral obstruction (UUO) in adult animals, the developing kidney responds very differently to obstruction. The transforming growth factor-2 (TGF-2) superfamily plays a central role in renal development, wound healing, cell survival, phenotypic epithelial-mesenchymal transition (EMT), and fibrosis. This research plan will utilize a newly developed murine model to study the renal cellular response of the TGF-2 superfamily in regulating injury and recovery from partial UUO in the neonatal mouse, whose renal development is comparable to that of a 20-week human fetus. The model permits study of injury and recovery by the obstructed kidney, and compensation by the contralateral kidney. A combination of mutants and inhibitors of critical components of TGF-21 signaling, as well as of counter-regulatory bone morphogenetic protein-7 (BMP- 7) will be used to elucidate molecular mechanisms. Extracellular TGF-21 will be decreased by administration of decorin; TGF-21 receptor activity will be investigated by selective inhibition of ALK5; while TGF-21 intracellular signaling will be studied in Smad3 null mice. Extracellular BMP-7 will be manipulated in 3 ways: reduced endogenous BMP-7 activity in the kielin/chordin-like protein (KCP) null mouse; increased endogenous BMP-7 in the uterine sensitization-associated gene-1 (USAG-1) null mouse; and exogenous recombinant BMP-7. Indices of renal maturation, proliferation, apoptosis, and EMT, as well as macrophages, fibroblasts, and collagen deposition will be studied by immunohistochemistry and quantitative morphometrics. In vitro cell culture studies will be performed in parallel, and information gained (stretch-induced modulation of intracellular or junctional proteins) will be applied to the animal studies. The combination of surgical relief of obstruction with manipulation of TGF-21 may lead to new biomarkers or therapies to test in children with obstructive nephropathy. PUBLIC HEALTH RELEVANCE: Half of all children with kidney failure are born with birth defects of the urinary tract, and the most common of these are due to obstruction to urine flow. The timing and indications for surgical intervention are unclear, and recovery is unpredictable. A new animal (mouse) model is proposed to study the major cellular mechanisms for injury to the newborn kidney, as well as to evaluate new therapies to enhance recovery.