PLEIOTROPIC EFFECTS OF PRORENIN RECEPOR IN COLLECTING DUCT AND INTRARENAL RAS ACTIVATION

肾素原受体在收集管和肾内 RAS 激活中的多效性作用

基本信息

批准号：
9306688
负责人：
Minolfa C Prieto
金额：
$ 33.86万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306688
关键词：
Address Angiotensin II Angiotensin II Receptor Angiotensin II Type 1 Receptor Blockers Angiotensin-Converting Enzyme Inhibitors Blood Pressure CREB1 gene Cardiovascular Diseases Cell Culture Techniques Cell membrane Cell surface Cells Chronic Chronic Kidney Failure Culture Media Cyclic AMP Data Development Diabetes Mellitus Diabetic Nephropathy Distal Duct (organ) structure Ductal Epithelial Cell End stage renal failure Enzymes Equilibrium Exhibits Fibrosis Gene Targeting Generations Genes Genetic Goals Histologic Hormones Hyperglycemia Hypertension In Vitro Inactive Renin Injury Kidney Knockout Mice Laboratories Lead Length Link Mediating Membrane Methodology Mission Molecular Mus Nephrons Organ Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Physiological Pre-Eclampsia Public Health Receptor Activation Regulation Renal Tissue Renin Renin-Angiotensin System Research Risk Risk Factors Role Signal Transduction Sodium Sodium Chloride Solid Streptozocin System Testing United States National Institutes of Health Water absorption base blood pressure regulation cell type defined contribution epithelial Na+ channel experimental study in vivo innovation knock-down mouse model nephrogenesis new therapeutic target novel novel therapeutics pleiotropism prevent prorenin receptor public health relevance receptor response small hairpin RNA urinary

项目摘要

DESCRIPTION (provided by applicant): Diabetes and hypertension are two major risk factors for chronic kidney disease. Inappropriate activation of the intrarenal renin-angiotensin system (the hormone system that regulates blood pressure and water balance, RAS) substantially increases risk and progression to renal injury. Current treatments targeting the RAS only slow, rather than halt the progression to chronic kidney disease. Therefore, we urgently need to understand the mechanisms which activate this system and lead to increased blood pressure and renal injury in order to develop new therapeutic targets to control the progression to end-stage organ damage. Our long- term goal is to define the contributions of the newly discovered prorenin receptor in the collecting duct to the pathogenesis of hypertension and renal injury and to introduce a paradigm-challenging concept which explains the interaction between the prorenin receptor and prorenin in the collecting duct which highlights the functional roles of this interaction in the regulation of sodium reabsorption, blood pressure, and development and progression of renal fibrosis in diabetes mellitus and hypertension. Our central hypothesis is that during hypertension and hyperglycemia, the interaction between the prorenin receptor and prorenin in the collecting duct contribute to increased blood pressure and to the development and progression to renal injury by mechanisms that are both dependent and independent of angiotensin II, the major effector hormone of the renin-angiotensin system. This hypothesis will be tested addressing the following specific aims: (1) Demonstrate that the prorenin receptor is required for the activation of prorenin produced in the collecting ducts; (2) Determine the functional consequences of the interaction between prorenin and soluble prorenin receptor in the collecting duct during angiotensin II-dependent hypertension; and (3) Demonstrate that prorenin-dependent activation of membrane bound prorenin receptor to collecting duct cells leads to renal fibrosis during Streptozotocin-induced hyperglycemia. We will attain these specific aims using a vertical and innovated approach which will include in vivo and in vitro experiments using a unique mouse model developed by our laboratory with a specific genetic deletion of the prorenin receptor in the collecting duct. Experiments will be assessed using integrated physiological, molecular and histological methodologies. The successful completion of the research proposed is of great significance because findings will provide definitive in vivo evidence of the functional role of the prorenin receptor in the collecting duct, which will providea rationale for the generation of novel drugs targeting this receptor. Understanding the mechanism of this novel pathway will be of relevance to public health because it will allow the optimization of treatment in conditions associated with augmented prorenin receptor-prorenin interaction such as hypertension, diabetes, and preeclampsia.

描述（由申请人提供）：糖尿病和高血压是慢性肾脏疾病的两个主要危险因素。不适当的激活对血压和水平平衡的激素系统（调节血压和水平的激素系统，RAS）的不当激活显着增加了风险和发展为肾损伤。目前针对RAS的治疗仅缓慢，而不是停止发展为慢性肾脏疾病。因此，我们迫切需要了解激活该系统并导致血压和肾脏损伤增加的机制，以开发新的治疗靶标，以控制终端器官损伤的进展。我们的长期目标是定义新发现的prorenin受体在收集导管中对高血压和肾脏损伤发病机理的贡献，并引入范式挑战范围的概念，该概念解释了prorenin受体和prorenin在收集管道中的相互作用，该概念突出了该功能的作用。糖尿病和高血压中肾纤维化的调节，血压以及肾纤维化的发育和发展中的相互作用。我们的中心假设是在高血压和高血糖症中，在收集管道中，prorenin受体和prorenin之间的相互作用有助于血压升高，并通过依赖且与血管紧张素II的机制（肾素 - 血管紧张素系统的主要效应激素）相关的机制发展和发展为肾脏损伤。该假设将进行检验，以解决以下特定目的：（1）证明prorenin受体是在收集管道中激活prorenin所必需的；（2）确定在血管紧张素II依赖性高血压期间，在收集管道中，核和可溶性prorenin受体之间相互作用的功能后果；（3）证明膜结合的prorenin受体对收集管道细胞的促肾依赖性激活导致链蛋白酶诱导的高血糖期间导致肾纤维化。我们将使用垂直和创新的方法实现这些特定目标，其中包括体内和体外实验，使用我们实验室开发的独特小鼠模型，并在收集管道中对prorenin受体的特定遗传缺失进行了特定的遗传缺失。实验将使用综合的生理，分子和组织学方法来评估。提出的研究的成功完成至关重要，因为发现将为prorenin受体在收集导管中的功能作用提供明确的体内证据，这将提供针对该受体的新药物的基本原理。了解这种新途径的机制将与公共卫生有关，因为它将允许在与增强的prorenin受体 - 普罗纳蛋白相互作用（例如高血压，糖尿病和先兆子痫相关）相关的条件下优化治疗。