ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION

盐敏感或盐依赖的血压升高在大多数人中都很明显。控制钠排泄的肾脏缺陷被认为是盐依赖型高血压发展的主要因素。每一位项目负责人在过去10年中所做的工作提供了关于肾脏内皮素(ET-1)系统在控制钠排泄、肾脏血流动力学和血压方面的强大作用的重要信息，表明内皮素系统在生理意义上与肾素-血管紧张素系统相媲美。这包括重要的证据表明，即使没有高血压，高盐饮食也会对肾脏血流动力学功能产生重大影响。我们的研究使我们假设ETB受体的功能与ETA受体强大的血管收缩和促高血压作用相平衡。然而，关于决定这些受体系统活性的特定条件，我们根本没有足够的信息可用。目前的建议建立在研究表明，ETA受体在促进高血压和相关的终末器官损伤方面发挥作用，而ETB受体功能的缺乏导致对盐诱导的高血压的敏感性增加。因此，本项目的目标是利用从基因水平到整体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ET-1活性的途径。 目前的计划由四个项目组成。每个项目都从血液动力学和肾小管功能的角度探讨内皮素系统的一个独特方面，并将阐明受体亚型对炎症、氧化应激、肾脏血流动力学和肾小管功能的特定作用；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脏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面机制，以便提供临床相关信息。

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.