Renin-ANG System in Morphogenesis of Renal Medulla

描述（由申请人提供）：先天性肾脏和泌尿道异常（CAKUT）是儿童肾衰竭的主要原因。为了开发更有效的预防和治疗干预措施，重要的是更好地了解CAKUT的分子发病机制。发育中的肾脏分支形态发生包括输尿管芽（UB）及其子集合管的生长和分支。即使是这个过程的效率和/或准确性方面的细微缺陷，也会对肾脏的最终发育产生深远的影响。肾髓质和乳头的正常发育需要肾素-血管紧张素系统（RAS），因为小鼠中编码RAS组分的基因突变引起肾乳头发育不全、肾积水和尿浓缩缺陷。此外，UB分支和周围间充质基质表达血管紧张素原（ACT）和血管紧张素（ANG）IIAT 1/AT 2受体。这些发现表明，UB衍生的上皮细胞是ANG II在后肾发育过程中作用的靶点。在本提案中，我们将检验ANG II调节肾集合系统发育的早期和晚期步骤的总体假设。在目标1中，我们将利用在UB中表达绿色荧光蛋白的AGT缺陷小鼠来检验以下假设：在早期后肾发育期间，UB分支形态发生需要内源性ANG II。目的2将检验ANG II在后肾发育后期刺激乳头状突起形成的假设。目的3将检验AT 1受体在AT 1缺陷小鼠UB中的转基因表达拯救UB生长和分支的假设。目的4将描述RAS和基质因子之间的相互作用，这些因子对UB分支形态发生和乳头状突起的发育很重要。拟议的研究结果应产生新的知识的作用，血管紧张素II在UB/乳头状生长和发展。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.