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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：
8800966
负责人：
Minolfa C Prieto
金额：
$ 35.15万
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/8800966
关键词：
Address Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin-Converting Enzyme Inhibitors Binding 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 Drug Targeting Duct (organ) structure End stage renal failure Enzymes Equilibrium Exhibits Fibrosis Gene Targeting Generations Genes Genetic Goals Hormones Hyperglycemia Hypertension In Vitro Inactive Renin Injury Kidney 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 Hypertension Renal Tissue Renin Renin-Angiotensin System Research Risk Risk Factors Role Signal Transduction Sodium Sodium Chloride Solid Staging Streptozocin System Testing Water absorption base blood pressure regulation cell type defined contribution epithelial Na+ channel in vivo innovation mouse model nephrogenesis new therapeutic target novel novel therapeutics prevent prorenin receptor public health relevance receptor research study 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大危险因素。肾内肾素-血管紧张素系统（调节血压和水分平衡的激素系统，RAS）的不适当激活大大增加了肾损伤的风险和进展。目前针对RAS的治疗只能减缓，而不是停止慢性肾脏疾病的进展。因此，我们迫切需要了解激活该系统并导致血压升高和肾损伤的机制，以便开发新的治疗靶点来控制终末期器官损伤的进展。我们的长期目标是确定新发现的聚肾管中prorenin受体在高血压和肾损伤发病机制中的作用，并引入一个具有挑战性的概念，解释聚肾管中prorenin受体和prorenin之间的相互作用，并强调其功能作用