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: 8125044
• 负责人: DAVID M POLLOCK
• 金额: $ 223.44万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125044
• 关键词: ENDOTHELIN; CONTROL; RENAL; HEMODYNAMIC; EXCRETORY

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.

大多数人群都存在明显的盐敏感性或盐依赖性血压升高。已知肾脏控制钠排泄的缺陷是盐依赖性高血压发生的主要原因。每位项目负责人在过去 10 年中所做的工作提供了关于肾内皮素 (ET-1) 系统在控制钠排泄、肾血流动力学和血压方面的强大作用的重要信息，表明内皮素系统可与肾内皮素系统相媲美。肾素-血管紧张素系统的生理意义。这包括重要的证据表明，即使没有高血压，高盐饮食也会对肾血流动力学功能产生显着影响。我们的研究使我们推测 ETB 受体的功能是抵消 ETA 受体强大的血管收缩和促高血压作用。然而，关于决定这些受体系统活性的具体条件，根本没有足够的信息。目前的提议建立在研究表明 ETA 受体在促进高血压和相关终末器官损伤中发挥作用的基础上，而 ETB 受体功能的缺乏会导致对盐诱发高血压的敏感性增加。因此，本项目的目标是通过从基因水平到整体动物模型的一系列实验方法确定ET-1的生理作用，全面探索肾脏中ET-1活性的调节途径。 当前计划由四个项目组成。每个项目都探索内皮素系统在血流动力学和肾小管功能方面的独特方面，并将阐明受体亚型对炎症、氧化应激、肾血流动力学和肾小管功能的特异性作用；特别强调影响钠排泄和血压控制的因素。这些研究有望为调节肾钠排泄的主要系统提供重要的新见解。特别是，该计划将研究控制 ET-1 释放和受体特异性作用的全方位机制，以提供临床相关信息。