Tubuloglomerular feedback and salt-sensitive hypertension

肾小球反馈和盐敏感性高血压

基本信息

批准号：
8737891
负责人：
RUISHENG LIU
金额：
$ 13.34万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737891
关键词：
7-nitroindazole Acute Address Adenosine Adult Affect American Angiotensin II Animal Model Animals Attenuated Blood Blood Pressure Cells Cytoskeleton Data Development Distal Equilibrium Excretory function Exhibits Exons Failure Feedback Figs - dietary Generations Glomerular Filtration Rate Homeostasis Human Hypertension Image In Vitro Ingestion Integrins Juxtaglomerular Apparatus Kidney Knock-out Knockout Mice Macula densa Mechanics Mediating Microdissection Microfilaments Modeling Morbidity - disease rate Nephrons Neurons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Patients Play Population Process Protein Isoforms RNA Splicing Regulation Residual state Resistance Role Signal Transduction Sodium Sodium Chloride Stimulus Surface System Techniques Testing Tissues Tubular formation Variant Water arteriole base cardiovascular risk factor falls hemodynamics in vivo laser capture microdissection mouse model novel prevent public health relevance research study response restoration salt intake salt sensitive salt sensitive hypertension shear stress

项目摘要

DESCRIPTION (provided by applicant): Hypertension affects over 25% of the adults and is a major cardiovascular risk to our population. More than half of hypertensive humans are salt-sensitive and have significant blood pressure fluctuations when salt intake is altered. However, the mechanisms for salt-sensitivity are not clear. Increases in glomerular filtration rate (GFR) play a vital role in the rapid elimination of sodium following acute volume expansion associated with ingestion of a sodium load, thereby contributing to restoration of sodium and water balance which maintains normal blood pressure. This GFR response is blunted in humans and in animal models with salt-sensitive hypertension. Tubuloglomerular feedback (TGF) is an essential regulator of GFR. Increasing tubular flow initiates a TGF response mediated by raising NaCl delivery to the macula densa (MD), which triggers signals that enhance the tone of the afferent arterioles and thereby reduces GFR. This fall in GFR helps restore MD flow rate toward normal and prevents marked changes in NaCl excretion. However, in persistent situations such as experimental or postprandial volume expansion, intrinsic mechanisms reset TGF, which shifts the operating point to a higher flow rate thus allowing GFR to rise. TGF resetting could facilitate the excretion of salt and water via mechanisms that may be dependent on suppression of angiotensin II and increased activity of the nitric oxide (NO) system. NO derived from the MD has been shown to dilate the afferent arteriole and blunt TGF. This NO is mainly produced by neuronal NO synthase (nNOS), which is abundantly expressed in the MD. However, the roles of the MD-delivered NO and TGF in regulation of volume homeostasis are only assumptions from these experiments. We still do not know whether NO from the MD and TGF play any roles in control of salt-water balance and blood pressure, which is the focus of this proposal. In this proposal, we will test the hypothesis that nNOS¿ in the MD is a salt sensitive isoform, which contributes to enhanced NO generation by the MD during high salt intake. Enhanced nNOS¿ activity blunts TGF and increases GFR, a mechanism which is essential in rapid elimination of a salt load and restoration of salt-water balance. Inadequate NO generation by the MD induces salt sensitive hypertension.

描述（由申请人提供）：高血压影响超过 25% 的成年人，是我国人口的主要心血管风险。超过一半的高血压患者对盐敏感，在摄入盐时血压会出现显着波动。对于盐敏感性的影响尚不清楚，肾小球滤过率（GFR）的增加在与摄入钠负荷相关的急性容量扩张后快速消除钠方面发挥着至关重要的作用，从而有助于维持正常血压的钠和水平衡的恢复在人类和患有盐敏感性高血压的动物模型中会减弱，肾小球反馈（TGF）是肾小球流量增加启动由 TGF 介导的重要调节剂。增加 NaCl 向致密斑 (MD) 的输送，从而触发增强传入小动脉张力的信号，从而降低 GFR。GFR 的下降有助于将 MD 流速恢复到正常水平。然而，在实验或餐后容量扩张等持续情况下，内在机制会重置 TGF，从而将工作点转移到更高的流速，从而使 GFR 重置可能会促进。盐和水的排泄机制可能依赖于血管紧张素 II 的抑制和来自 MD 的一氧化氮 (NO) 系统活性的增加，已被证明可以扩张传入小动脉并钝化 TGF。然而，MD 传递的 NO 和 TGF 在调节体积稳态中的作用只是这些实验的假设。仍然不知道来自 MD 和 TGF 的 NO 是否在控制盐水平衡和血压方面发挥任何作用，这是本提案的重点，在本提案中，我们将检验 nNOS 的假设。 MD 中的亚型是盐敏感亚型，在高盐摄入期间有助于 MD 增强 NO 生成。活性会减弱 TGF 并增加 GFR，这是快速消除盐负荷和恢复盐水平衡所必需的机制。MD 产生的 NO 不足会诱发盐敏感性高血压。