Integrating novel mechanisms controlling sodium excretion and blood pressure

整合控制钠排泄和血压的新机制

• 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
• 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

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， 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

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
• 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.

• DOI: 10.14814/phy2.15206
• 发表时间: 2022-03
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Hu C;Lakshmipathi J;Stuart D;Kohan DE
• 通讯作者: Kohan DE

SONAR propels endothelin A receptor antagonists to success.

SONAR 推动内皮素 A 受体拮抗剂取得成功。

• DOI: 10.1038/s41581-019-0169-9
• 发表时间: 2019
• 期刊: Nature reviews. Nephrology
• 作者: Pollock,JenniferS;Pollock,DavidM
• 通讯作者: Pollock,DavidM

G protein-coupled estrogen receptor 1 regulates renal endothelin-1 signaling system in a sex-specific manner.

• DOI: 10.3389/fphys.2023.1086973
• 发表时间: 2023
• 期刊: Frontiers in physiology
• 影响因子: 4

Nephron prorenin receptor deficiency alters renal medullary endothelin-1 and endothelin receptor expression.

肾单位肾素原受体缺乏会改变肾髓质内皮素-1 和内皮素受体的表达。

• DOI: 10.33549/physiolres.933809
• 发表时间: 2018
• 期刊: Physiological research
• 影响因子: 2.1
• 作者: Ramkumar,N;Stuart,D;Abraham,N;Kohan,DE
• 通讯作者: Kohan,DE