Mechanisms of Renoprotection by Relaxin in Hypertension

松弛素在高血压中的肾脏保护机制

• 批准号: 8690044
• 负责人: Jennifer M Sasser
• 金额: $ 12.68万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690044
• 关键词: Address; Adverse effects; Affect; Agonist; Angiotensin II; Antihypertensive Agents; Antioxidants; Basic Science; Biological Availability; Blood Pressure; Chronic; Chronic Kidney Failure; Clinical Data; Clinical Sciences; Cost of Illness; Data; Disease; End stage renal failure; Endothelin; Endothelin B Receptor; Endothelin-1; Environment; Enzymes; Experimental Models; Florida; Foundations; Goals; Health; Hypertension; Hypotension; Incidence; Injury; Kidney; Kidney Diseases; Knowledge; Measures; Mediating; Mentors; Molecular; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Organ; Oxidative Stress; Patients; Peptides; Pharmacologic Actions; Phosphorylation; Physiology; Prevention; Property; Rattus; Reactive Oxygen Species; Regulation; Relaxin; Renal function; Research; Research Personnel; Role; System; Testing; Therapeutic; Training Programs; Universities; Up-Regulation; Work; base; career; career development; cost; design; functional genomics; gene therapy; hemodynamics; hypertension treatment; improved; inhibitor/antagonist; interest; novel; novel therapeutic intervention; peptide hormone; prevent; programs; receptor; research study; response

DESCRIPTION (provided by applicant): Recent studies indicate that the peptide hormone relaxin has multiple beneficial actions in the cardio-renal system under pathological conditions due to its vasodilatory, anti-fibrotic, and angiogenic properties. Therefore, relaxin holds great promise as a novel therapeutic intervention for patients with kidney disease. The tremendous therapeutic potential of relaxin in hypertension induced chronic kidney disease can only be determined by first carefully investigating the actions of this peptide in experimental models of disease. This proposal will determine the molecular mechanisms of the renoprotective actions of relaxin during hypertension by testing the hypothesis that relaxin stimulates the endothelin B receptor - nitric oxide pathway to lower blood pressure and prevent progression of renal injury in hypertensive rats. Proposed studies will also investigate the potential for relaxin gene therapy in the treatment of hypertension and chronic kidney disease. This novel proposal will investigate these specific aims: (1) to test the hypothesis that relaxin increases NO bioavailability during hypertension via increased NOS activity and reduced oxidative stress, (2) to determine if the renoprotective effects of relaxin are mediated by activation of endothelin type B (ETB) receptors, and (3) to determine if kidney specific upregulation of relaxin is antihypertensive and can prevent end organ damage. The candidate will use the work described in this proposal as the basis of an independent line of research into the role of relaxin in the prevention of chronic kidney disease, and a comprehensive training program has been designed to move the applicant to a career as an independent investigator. Dr. Chris Baylis, an exceptional renal physiologist and mentor, will serve as the candidate's mentor. Her expertise and the superb environment of the University of Florida, rich in clinical and basic sciences, will offer the candidate the best opportunity for achieving her goal of becoming an independent investigator in the field of renal physiology.

描述（由申请人提供）：最近的研究表明，肽激素松弛素由于其血管舒张、抗纤维化和血管生成特性，在病理条件下在心肾系统中具有多种有益作用。因此，松弛素作为肾脏疾病患者的新型治疗干预具有很大的前景。松弛素在高血压引起的慢性肾病中的巨大治疗潜力只能通过首先仔细研究这种肽在疾病实验模型中的作用来确定。本研究拟通过验证松弛素刺激内皮素B受体-一氧化氮通路降低高血压大鼠血压并阻止肾损伤进展的假设，确定松弛素在高血压期间肾保护作用的分子机制。拟议的研究还将调查松弛素基因治疗的潜力， 治疗高血压和慢性肾病。这一新的提案将探讨这些具体目标：（1）检验松弛素通过增加NOS活性和降低氧化应激而增加高血压期间NO生物利用度的假设，（2）确定松弛素的肾保护作用是否由内皮素B型（ET B）受体的活化介导，以及（3）确定松弛素的肾特异性上调是否是抗高血压的并且可以防止终末器官损伤。候选人将使用本提案中描述的工作作为松弛素在预防慢性肾脏疾病中的作用的独立研究路线的基础，并设计了一个全面的培训计划，以使申请人成为独立的研究者。克里斯贝利斯博士，一个特殊的肾脏生理学家和导师，将担任候选人的导师。她的专业知识和佛罗里达大学的一流环境，丰富的临床和基础科学，将为候选人提供实现她成为肾生理学领域独立研究者的目标的最佳机会。