Prorenin Receptor Mediates Early Changes in Diabetic Kidney

肾素原受体介导糖尿病肾脏的早期变化

• 批准号: 9086431
• 负责人: Helmy M Siragy
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2017-07-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086431
• 关键词: Accounting; Albuminuria; Attenuated; Cessation of life; Chronic Kidney Failure; Complement; Complications of Diabetes Mellitus; Conscious; Data; Development; Diabetes Mellitus; Dimerization; EMSA; End stage renal failure; Fibrosis; Fluorescence Resonance Energy Transfer; Goals; Health; Health Care Costs; Heterodimerization; Hyperglycemia; In Vitro; Inflammation; Injury; Kidney; Kidney Diseases; Lasers; Lead; Mediating; Microdialysis; Microscopy; Molecular; Morphology; Pathologic; Persons; Physiological; Process; Rattus; Receptor, Angiotensin, Type 1; Regulation; Renal function; Renin; Renin-Angiotensin System; Research; Scanning; Signal Pathway; Signal Transduction; Small Interfering RNA; Streptozocin; Techniques; Testing; United States; Up-Regulation; base; cardiovascular disorder risk; chromatin immunoprecipitation; diabetic; in vivo; interstitial; kidney cell; knock-down; novel; novel therapeutic intervention; programs; prorenin receptor; receptor; receptor expression; small hairpin RNA; vacuolar H+-ATPase; Accounting; Albuminuria; Attenuated; Cessation of life; Chronic Kidney Failure; Complement; Complications of Diabetes Mellitus; Conscious; Data; Development; Diabetes Mellitus; Dimerization; EMSA; End stage renal failure; Fibrosis; Fluorescence Resonance Energy Transfer; Goals; Health; Health Care Costs; Heterodimerization; Hyperglycemia; In Vitro; Inflammation; Injury; Kidney; Kidney Diseases; Lasers; Lead; Mediating; Microdialysis; Microscopy; Molecular; Morphology; Pathologic; Persons; Physiological; Process; Rattus; Receptor, Angiotensin, Type 1; Regulation; Renal function; Renin; Renin-Angiotensin System; Research; Scanning; Signal Pathway; Signal Transduction; Small Interfering RNA; Streptozocin; Techniques; Testing; United States; Up-Regulation; base; cardiovascular disorder risk; chromatin immunoprecipitation; diabetic; in vivo; interstitial; kidney cell; knock-down; novel; novel therapeutic intervention; programs; prorenin receptor; receptor; receptor expression; small hairpin RNA; vacuolar H+-ATPase

DESCRIPTION (provided by applicant): (Pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system. The exact physiologic and pathologic functions of PRR are not established yet. Our preliminary studies in vitro and in vivo demonstrated that hyperglycemia increases PRR expression and activity, a process that is regulated by angiotensin AT1 receptor (AT1R), mainly via their heterodimerization. As a result of the interaction between AT1R and PRR there is upregulation of V-ATPase and Wnt3a expression and activity leading to renal inflammation fibrosis and albuminuria. In vivo intrarenal interstitia administration of PRR shRNA or Wnt3a shRNA reduced albuminuria, renal inflammation and morphologic changes associated with hyperglycemia. Based on these data, it is likely that PRR directly contributes to development of hyperglycemia-induced renal injury. The long-term goal of our research program is 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 AT1R, vacuolar-ATPase (V-ATPase) and Wnt3a, and lead to development of hyperglycemia- induced renal disease. To achieve this goal, we will utilize a rationale and novel integrated approaches, consisting of in vivo studies utilizing combined knockdown of renal PRR, V-ATPase or Wnt3a and renal interstitial microdialysis technique in conscious normoglycemic and hyperglycemic streptozotocin- induced diabetes rats. These studies will be complemented by state-of-the-art in vitro cellular and molecular techniques utilizing siRNA, shRNA, EMSA, ChIP assays, and Laser Scanning Confocal FRET microscopy to rigorously test the proposed hypothesis. Based on our recent observations and preliminary data, the central hypothesis of this proposal is that in presence of hyperglycemia, PRR activity is increased by dimerization with AT1R leading to enhanced expression and activity of V-ATPase and Wnt3a signaling pathways to induce renal inflammation, fibrosis and albuminuria. We will pursue the following specific aims: Aim 1: To test the hypothesis that hyperglycemia increases PRR expression and activity and its heterodimerization with AT1R, leading to renal inflammation, fibrosis and albuminuria. Aim 2: To test the hypothesis that hyperglycemia- enhanced PRR activity mediates renal injury by increasing the expression and activity of V-ATPase. Aim 3: To test the hypothesis that hyperglycemia-enhanced PRR activity contributes to renal injury via increased expression and activity of Wnt3a. These studies are expected to identify novel pathophysiologic mechanisms related to PRR and could lead to development of new therapeutic strategies for treating hyperglycemia-induced renal disease.

描述（由申请人提供）：（ Pro）肾素受体（PRR）是肾素 - 血管紧张素系统的新成分。尚未确定PRR的确切生理和病理功能。我们在体外和体内的初步研究表明，高血糖会增加PRR的表达和活性，PRR的表达和活性是由血管紧张素AT1受体（AT1R）调节的过程，主要是通过其异二聚化来调节的。由于AT1R与PRR之间的相互作用，V-ATPase和Wnt3a表达的上调以及活性导致肾脏炎症纤维化和蛋白尿。体内体内跨间隔prr shRNA或Wnt3a shRNA减少蛋白尿，肾脏炎症和与高血糖相关的形态变化。基于这些数据，PRR可能直接有助于高血糖引起的肾脏损伤的发展。我们的研究计划的长期目标是阐明有助于调节PRR表达和功能的体外和体内新型机制，并评估该受体与AT1R，液泡ATPase（V-ATPase（V-ATPase）和Wnt3a的病理学意义，并导致高糖类诱导的肾脏疾病的发展。为了实现这一目标，我们将利用一种基本原理和新颖的综合方法，包括利用肾脏PRR，V-ATPase或Wnt3A的组合敲低研究以及肾脏间质微量透析技术在有意识的正常糖症和高血糖型脱肽蛋白酶诱导的糖尿病的肾脏中。这些研究将通过使用siRNA，SHRNA，EMSA，CHIP分析和激光扫描共共聚焦FRET显微镜进行严格测试提出的假设的最新研究中的最新体外细胞和分子技术补充。根据我们最近的观察和初步数据，该提议的核心假设是在存在高血糖的情况下，PRR活性是 通过用AT1R二聚化而增加，从而增强了V-ATPase和Wnt3a信号通路的表达和活性，以诱导肾脏炎症，纤维化和蛋白尿症。我们将追求以下特定目的：目标1：测试高血糖的假设，即高血糖会增加PRR的表达和活性及其与AT1R的异二聚化，从而导致肾脏炎症，纤维化和蛋白尿。目的2：测试假说，高血糖增强的PRR活性通过增加V-ATPase的表达和活性来介导肾脏损伤。目的3：检验以下假设：高血糖增强的PRR活性通过增加WNT3A的表达和活性导致肾脏损伤。这些研究预计将确定与PRR相关的新型病理生理机制，并可能导致开发用于治疗高血糖引起的肾脏疾病的新治疗策略。