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Integrating novel mechanisms controlling sodium excretion and blood pressure

整合控制钠排泄和血压的新机制

基本信息

批准号：
10267370
负责人：
DAVID M POLLOCK
金额：
$ 1.85万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10267370
关键词：
ARNTL gene Acute Adult Animal Model Automobile Driving Behavior Biological Blood Pressure Blood Vessels Body Fluids Cardiovascular Diseases Cardiovascular system Catheters Cholesterol Chronic Kidney Failure Circadian Rhythms Circadian desynchrony Consumption Cues Defect Development Disease Disease Progression Eating Electrolytes Endothelin Endothelin-1 Equilibrium Estrogens Event Excretory function Female Foundations Functional disorder Future Gene Expression Genes Glomerular Filtration Rate Goals Gonadal Steroid Hormones Health Hispanics Homeostasis Hormones Hour Human Hypertension Impairment Implant Infusion Technique Intravenous Investigation Kidney Knock-out Knockout Mice Lead Learning Measures Metabolic Metabolic Diseases Modeling Mus Nature Organism Pathway interactions Periodicity Peripheral Phase Phenotype Physiological Play Police officer Publishing Pump Rattus Receptor Activation Renal function Reporting Risk Risk Factors Role Sex Differences Sodium Sodium Chloride Stroke System Telemetry Testing Testosterone Time Tissues Treatment Protocols Triglycerides Water Western World Woman Work blood pressure regulation cardiovascular disorder risk cardiovascular risk factor circadian circadian regulation clinically relevant design dietary salt experimental study feeding high salt diet inflammatory marker insight insulin sensitivity interest male men mindfulness molecular clock mouse model negative affect novel novel therapeutic intervention novel therapeutics programs receptor receptor function response salt intake salt sensitive hypertension sex shift work suprachiasmatic nucleus transcription factor western diet

项目摘要

PROJECT 1 SUMMARY High salt diets have grown increasingly prevalent in the Western world and contribute to increased risk of cardiovascular disease including hypertension and chronic kidney disease. The renal endothelin system has emerged an important control system for sodium and water excretion and so derangements in this pathway could provide insights for potential new therapeutic approaches. Abnormalities in circadian rhythms are associated with increased risk of a wide range of metabolic, cardiovascular, and other disorders. Furthermore, cardiovascular events are far more prevalent at specific times of day suggesting a circadian contribution of cardiovascular disease. Recent studies have revealed that the peripheral molecular clock regulates water and sodium homeostasis, but the underlying mechanisms are unclear. We recently observed that Bmal1, a circadian-dependent transcription factor, loses its rhythmicity under high salt diet conditions and appears to be regulated by the endothelin (ET) system. Rats lacking a functional ETB receptor have a severely delayed response to an acute salt load that is dependent upon the time of day. Therefore, our goal is to determine the relationship between the ET-1 system and circadian regulation of sodium excretion. Aim 1 is designed to test the hypothesis that ETB receptor activation suppresses Bmal1 to facilitate sodium excretion and account for diurnal renal sodium handling. Aim 2 will test the hypothesis that Bmal1 functions to suppress sodium excretion. We have also uncovered that female rats are protected against the loss of excretory control in a diurnal manner that may be due to differences in sex steroid function. Thus, Aim 3 will test the hypothesis that the balance between effects of testosterone and estrogen effects on vascular ETA receptor function accounts for sex differences in diurnal control of sodium excretion.

项目1概要高盐饮食在西方世界越来越普遍，并增加了患糖尿病的风险。心血管疾病，包括高血压和慢性肾病。肾脏内皮素系统具有出现了一个重要的控制系统，钠和水的排泄，因此在这一途径的紊乱可以为潜在的新治疗方法提供见解。昼夜节律的异常是与多种代谢、心血管和其他疾病的风险增加相关。此外，委员会认为，心血管事件在一天中的特定时间更为普遍，这表明心血管疾病最近的研究表明，外周分子钟调节水，钠稳态，但潜在的机制尚不清楚。我们最近观察到，昼夜节律依赖性转录因子，在高盐饮食条件下失去其节律性，由内皮素（ET）系统调节。缺乏功能性ETB受体的大鼠出现严重延迟的对急性盐负荷的反应取决于一天中的时间。因此，我们的目标是确定 ET-1系统与钠排泄的昼夜调节之间的关系。Aim 1旨在测试 ETB受体激活抑制Bmal 1促进钠排泄并解释昼夜肾钠处理。目的2将检验Bmal 1功能抑制钠离子的假设排泄我们还发现，雌性大鼠的排泄控制在一个特定的环境中得到保护，昼夜方式，可能是由于性类固醇功能的差异。因此，目标3将检验以下假设：睾酮和雌激素对血管ETA受体功能的影响之间的平衡解释了昼夜钠排泄控制的性别差异。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-term circadian disruption shortens life span and dampens blood pressure diurnal rhythms in stroke-prone spontaneously hypertensive rats.

长期昼夜节律紊乱会缩短易发生中风的自发性高血压大鼠的寿命并抑制血压昼夜节律。

DOI：
10.1152/ajpheart.00055.2023
发表时间：
2023
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Ramsey,AnneM;Stowie,Adam;Hill,Atlantis;Ellis,Ivory;Rhodes,MeganK;Pollock,DavidM;Davidson,AlecJ
通讯作者：
Davidson,AlecJ

Profiling renal sodium transporters in mice with nephron Ift88 disruption: Association with sex, cysts, and blood pressure.