ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION

内皮素对肾脏血流动力学和排泄功能的控制

• 批准号: 8464198
• 负责人: DAVID M POLLOCK
• 金额: $ 213.61万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464198
• 关键词: Angiotensin II; Animal Model; Animals; Basic Science; Blood Pressure; Chronic; Clinical Trials; Defect; Development; Diabetic Nephropathy; Diet; Disease; Duct (organ) structure; Endothelin; Endothelin A Receptor; Endothelin Receptor; Endothelin-1; Endothelium; Equilibrium; Excretory function; Functional disorder; Future; Gene Expression; Genes; Genetic; Goals; Health; Human; Hypertension; Inflammation; Inflammatory; Infusion procedures; Investigation; Kidney; Kidney Diseases; Malignant Hypertension; Marketing; Measures; Microcirculation; Mitogen-Activated Protein Kinases; Modeling; Nature; Organ; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Patients; Peripheral Nerves; Pharmaceutical Preparations; Phase; Physiological; Play; Population; Production; Pulmonary Hypertension; Refractory; Renal function; Renin-Angiotensin System; Research; Research Personnel; Role; Series; Signal Transduction; Sodium; Sodium Chloride; System; Tissues; Tubular formation; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Work; autocrine; base; blood pressure regulation; clinically relevant; computerized data processing; effective therapy; hemodynamics; hypertension treatment; inhibitor/antagonist; insight; novel therapeutic intervention; paracrine; programs; receptor; receptor function; salt sensitive; vasoconstriction

Salt-sensitivity or salt-dependent elevations in blood pressure are evident in a majority of the human population. Renal defects in the control of sodium excretion are known to be major contributors to the development of salt-dependent hypertension. Work conducted by each of the Project Leaders over the past 10 years has provided important Information about the powerful role of the renal endothelin (ET- 1) system in the control of sodium excretion, renal hemodynamics, and blood pressure indicating that the endothelin system rivals the renin-angiotensin system in physiological significance. This includes important evidence that a high salt diet, even without hypertension, has a significant influence on renal hemodynamic function. Our studies have led us to hypothesize that the ETB receptor functions as a counter-balance to the powerful vasoconstrictor and pro-hypertensive actions of the ETA receptor. However, there is simply not enough information available about the specific conditions that determine the activity of these receptor systems. The current proposal builds on studies demonstrating that the ETA receptor plays a role in promoting hypertension and associated end-organ damage while a lack of ETB receptor function results in increased sensitivity to salt-induced hypertension. Therefore, the goal of the current Program Project is to determine the physiological actions of ET-1 using an array of experimental approaches ranging from the gene level to whole animal models to comprehensively explore the pathways regulating ET-1 activity in the kidney. The current Program is made of four Projects. Each project explores a unique aspect of the endothelin system in terms of both hemodynamics and tubular function and will elucidate the receptor subtype specific actions on inflammation, oxidative stress, renal hemodynamics and tubular function; a particular emphasis is on factors that influence the control of sodium excretion and blood pressure. These studies are expected to provide important new insight into a major system that regulates renal sodium excretion. In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information.

在大多数人口中，血压的盐敏感性或盐依赖性升高是显而易见的。控制钠排泄控制中的肾脏缺陷已知是盐依赖性高血压发展的主要因素。在过去的10年中，每个项目负责人进行的工作提供了有关肾脏内皮素（ET-1）系统在控制钠排泄，肾脏血液动力学和血压中的强大作用的重要信息，表明内皮素系统在物理学意义上与肾素 - 血管紧张素系统相媲美。这包括重要证据表明，即使没有高血压，高盐饮食也会对肾脏血流动力功能产生重大影响。我们的研究使我们假设ETB受体起着与ETA受体的强大血管收缩和促甲状管合作作用的反平衡。但是，根本没有关于确定这些受体系统活动的特定条件的足够信息。当前的建议基于研究表明，ETA受体在促进高血压和相关的最终器官损伤中起作用，而缺乏ETB受体功能会导致对盐诱导的高血压的敏感性提高。因此，当前程序项目的目标是使用从基因水平到整个动物模型的一系列实验方法来确定ET-1的生理作用，以全面探索调节肾脏中ET-1活性的途径。 当前程序由四个项目组成。每个项目都根据血液动力学和管状功能探讨了内皮素系统的独特方面，并将阐明受体亚型对炎症，氧化应激，肾脏血液动力学和管状功能的特定作用；特别强调的是影响控制钠排泄和血压的因素。预计这些研究将为调节肾脏钠排泄的主要系统提供重要的新见解。特别是，该程序将研究控制ET-1释放和受体特定动作的全部机制，以提供临床相关的信息。