Congenital abnormalities of the kidney and urinary tract (CAKUT) are the major cause of renal failure in childhood. In order to develop more effective preventive and therapeutic interventions, it is important to better understand the molecular pathogenesis of CAKUT. Branching morphogenesis in the developing kidney involves growth and branching of the ureteric bud (UB) and its daughter collecting ducts. Even subtle defects in the efficiency and/or accuracy of this process have profound effects on the ultimate development of the kidney. The renin-angiotensin system (RAS) is required for the proper development of the renal medulla and papilla, since mutations in the genes encoding components of the RAS in mice cause renal papillary hypoplasia, hydronephrosis, and urinary concentrating defect. In addition, the UB branches and surrounding mesenchymal stroma express angiotensinogen (ACT) and angiotensin (ANG) IIAT1/AT2 receptors. These findings imply that UB-derived epithelia are targets for ANG II actions during metanephric kidney development. In this proposal, we will test the overall hypothesis that ANG II regulates both early and late steps of renal collecting system development.
In Aim 1, we will utilize AGT-deficient mice expressing green fluorescent protein in the UB to test the hypothesis that endogenous ANG II is required for UB branching morphogenesis during early metanephric development.
Aim 2 will test the hypothesis that ANG II stimulates papillogenesis during late metanephric development.
Aim 3 will test the hypothesis that transgenic expression of AT1 receptor in the UB of AT1-deficient mice rescues UB growth and branching.
Aim 4 will characterize the cross-talk between the RAS and stromal factors important for UB branching morphogenesis and papillary development. The results of the proposed studies should yield new knowledge on the role of ANG II in UB/papillary growth and development. Such information can be utilized for the design of interventional strategies aimed at the prevention and treatment of CAKUT. ? ? ?
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