(Pro)renin receptor and renovascular hypertension

描述（申请人提供）：（Pro）肾素受体（PRR）是新发现的肾素-血管紧张素系统的组分。最近的研究表明，该受体与液泡H+ ATP酶（V-ATP酶）和Wnt信号通路的相互作用。然而，PRR的确切生理和病理功能尚未确定。PRR的完全缺失是致命的，并且条件性敲除或其特异性阻断剂的不可用使得研究该受体变得困难。我们的初步研究结果表明，低钠摄入和肾动脉夹闭可导致2肾1夹高血压大鼠模型（2K 1C）肾脏PRR表达增加，PRR参与调节V-ATP酶、Wnt 3a（涉及经典2-catenin信号通路）和Wnt 7a（涉及非经典通路）的表达。基于这些数据，PRR可能参与肾脏疾病的发生或进展。本研究项目的长期目标是阐明PRR表达和功能调节的体外和体内新机制，并评估该受体与V-ATP酶和Wnt信号通路相互作用在高血压诱导的肾损伤发展中的病理意义。为了实现这一目标，我们将利用一个基本原理和新的综合方法，包括在体外和体内研究本地化的肾脏，包括国家的最先进的细胞和分子技术，siRNA和shRNA，激光扫描共聚焦FRET显微镜和体内微透析更严格地测试提出的想法。基于我们的初步数据，该建议的中心假设是，血管紧张素AT 1（AT 1 R）和AT 2（AT 2 R）受体通过其信号通路调节PRR的表达，PRR增强V-ATP酶，Wnt 3a和Wnt 7a的表达和功能，从而诱导2K 1C高血压大鼠模型的肾脏炎症和纤维化。我们将努力实现以下具体目标：目标1。检验PRR表达和活性通过AT 1 R-有丝分裂原活化蛋白激酶、核因子-：B（NF：B）和激活蛋白-1（AP-1）信号通路上调的假设。目标2.验证PRR表达和活性通过AT 2 R-一氧化氮（NO）-cGMP-蛋白激酶G（PKG）信号通路和这两种受体之间的物理相互作用（二聚化）下调的假设。目标3：在2K 1C高血压大鼠模型上验证V-ATPase介导PRR引起的肾损伤的假说。目标4。在2K 1C高血压大鼠模型中，为了验证PRR在肾脏中调节Wnt 3a和Wnt 7a表达并介导其导致炎症和纤维化的信号通路的假设。这些研究有望确定与PRR相关的新病理生理机制及其对肾损伤的作用，并可能导致开发治疗高血压诱导的肾病的新治疗策略。

DESCRIPTION (provided by applicant): (Pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system. Recent studies suggested interaction of this receptor with vacuolar H+ATPase (V-ATPase) and Wnt signaling pathways. However, the exact physiologicand pathologic functions of PRR are not established yet. Total deletion of PRR is lethal, and unavailability of conditional knockout or its specific blockers made it difficult to study this receptor. Our preliminary data demonstrated that renal PRR expression is increased in response to low sodium intake and renal artery clipping of 2-kidney-1-clip hypertension rat model (2K1C), and that PRR contributes to the regulation of expression of V-ATPase, Wnt3a (involving canonical-2-catenin signaling pathway) and Wnt7a (involving non-canonical pathway). Based on these data, it is likely that PRR is involved in development or progression of renal disease. The long-term goal of our research program to elucidate the in vitro and in vivo novel mechanisms contributing to the regulation of PRR expression and function and evaluate the pathological significance of this receptor interaction with V-ATPase and Wnt signaling pathways in development of hypertension-induced renal injury. To achieve this goal, we will utilize a rationale and novel integrated approaches, consisting of in vitro and in vivo studies localized to the kidney including state-of-the-art cellular and molecular techniques, siRNA and shRNA, Laser Scanning Confocal FRET microscopy and in vivo microdialysis to more rigorously test the proposed ideas. Based on our preliminary data, the central hypothesis of this proposal is that angiotensin AT1 (AT1R) and AT2 (AT2R) receptors regulate the expression of PRR via their signaling pathways and that PRR enhances the expression and function of V-ATPase, Wnt3a and Wnt7a to induce renal inflammation and fibrosis in 2K1C hypertension rat model. We will pursue the following specific aims: Aim 1. To test the hypothesis that PRR expression and activity are upregulated via AT1R-mitogen-activated protein kinase, nuclear factor-:B (NF:B), and activator protein-1 (AP-1) signaling pathways. Aim 2. To test the hypothesis that PRR expression and activity are downregulated via AT2R-nitric oxide (NO)-cGMP-protein kinase G (PKG) signaling pathway and through physical interaction (dimerization) between these two receptors. Aim 3. To test the hypothesis that V-ATPase mediates PRR induced renal injury in 2K1C hypertension rat model. Aim 4. To test the hypothesis that in the kidney, PRR regulates Wnt3a and Wnt7a expressions and mediates their signaling pathways leading to inflammation and fibrosis in 2K1C hypertension rat model. These studies are expected to identify novel pathophysiologic mechanisms related to PRR and its contribution to renal injury and could lead to development of new therapeutic strategies in treating hypertension-induced renal disease.