Renin-ANG System in Morphogenesis of Renal Medulla

描述（由申请人提供）：先天性肾脏和尿路异常（ckut）是儿童肾衰竭的主要原因。为了制定更有效的预防和治疗措施，更好地了解CAKUT的分子发病机制至关重要。肾发育中的分支形态发生涉及输尿管芽（UB）及其子集管的生长和分支。即使这个过程中效率和/或准确性上的细微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）对于肾髓质和乳头的正常发育是必需的，因为在小鼠中编码RAS成分的基因突变会导致肾乳头发育不全、肾积水和尿浓缩缺陷。此外，UB分支和周围间质间质表达血管紧张素原（ACT）和血管紧张素（ANG） IIAT1/AT2受体。这些发现表明ub源性上皮是后肾发育过程中ANG II作用的靶点。在本提案中，我们将测试ANG II调节肾脏收集系统发育的早期和后期步骤的总体假设。在Aim 1中，我们将利用在UB中表达绿色荧光蛋白的agt缺陷小鼠来验证在早期后肾发育过程中UB分支形态发生需要内源性ANG II的假设。目的2将检验在后肾发育后期ANG II刺激乳头形成的假设。目的3将验证AT1缺陷小鼠UB中AT1受体的转基因表达是否能挽救UB的生长和分支。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。拟议研究的结果应该对ANG II在UB/乳头生长发育中的作用有新的认识。这些信息可用于设计旨在预防和治疗CAKUT的干预战略。

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.