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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：
9068087
负责人：
RUISHENG LIU
金额：
$ 32.52万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068087
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 Health 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 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，当盐摄入量改变时，他们的血压会有明显的波动。然而，盐敏感性的机制尚不清楚。肾小球滤过率（GFR）的增加在钠负荷摄入引起的急性容量扩张后钠的快速清除中起着至关重要的作用，从而有助于恢复钠和水的平衡，维持正常血压。这种GFR反应在人类和盐敏感性高血压动物模型中减弱。管肾小球反馈（TGF）是GFR的重要调节因子。增加的管状血流通过增加向黄斑致密（MD）的NaCl递送介导TGF反应，从而触发信号，增强传入小动脉的张力，从而降低GFR。GFR的下降有助于将MD流速恢复到正常水平，并防止NaCl排泄的显著变化。然而，在持续的情况下，如实验或餐后体积膨胀，内在机制重置TGF，将工作点转移到更高的流量，从而使GFR上升。TGF复位可以促进