Renin-ANG System in Morphogenesis of Renal Medulla

描述(申请人提供)：先天性肾脏和尿路异常(CAKUT)是儿童肾功能衰竭的主要原因。为了开发更有效的预防和治疗干预措施，更好地了解CAKUT的分子发病机制是重要的。肾脏发育中的分支形态发生包括输尿管芽(UB)及其子代集合管的生长和分支。即使在这一过程的效率和/或准确性上的微小缺陷也会对肾脏的最终发育产生深远的影响。肾素-血管紧张素系统(RAS)是肾髓质和肾乳头正常发育所必需的，因为RAS的编码成分的基因突变会导致小鼠肾乳头发育不良、肾积水和尿液浓缩缺陷。此外，UB分支及周围间质表达血管紧张素原(ACT)和血管紧张素ⅡAT1/AT2受体。这些发现表明，UB来源的上皮细胞是后肾发育过程中Ang II作用的靶点。在这项提案中，我们将检验Ang II调节肾脏收集系统发育的早期和晚期的总体假设。在目标1中，我们将利用在UB表达绿色荧光蛋白的AGT缺陷小鼠来验证内源性Ang II在UB后肾发育早期分支形态发生中所需的假说。目的2验证Ang II在后肾发育后期刺激乳头形成的假说。目的3验证AT1受体在AT1基因缺陷小鼠尿路中的转基因表达可挽救尿路生长和分支的假说。目的4将描述RAS和间质因子之间的串扰，这些因子对UB分支、形态发生和乳头发育至关重要。拟议的研究结果应该会对Ang II在UB/乳头状细胞生长和发育中的作用产生新的认识。这些信息可用于设计旨在预防和治疗CAKUT的干预策略。

DESCRIPTION (provided by applicant): 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.