Modulation of the renal aldosterone endothelin feedback system by the clock protein PER1

时钟蛋白 PER1 对肾醛固酮内皮素反馈系统的调节

• 批准号: 10476060
• 负责人: Michelle L Gumz
• 金额: $ 10万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476060
• 关键词: Address; Aldosterone; Animals; Blood Pressure; Cadherins; Cell model; Chronic Kidney Failure; Clinical; Clock protein; Data; Diet; Distal; Duct (organ) structure; Electrolyte Balance; Endothelin; Endothelin A Receptor; Endothelin Receptor; Endothelin-1; Epidemic; Equilibrium; Exhibits; Feedback; Fluid Balance; Gene Expression; Genes; Goals; Healthcare; High Prevalence; Homeostasis; Human; Hypertension; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Lead; Link; Liquid substance; Measures; Mediating; Mineralocorticoids; Modeling; Molecular; Mus; Nephrons; Physiological; Physiology; Play; Process; Regulation; Renin; Role; Signal Transduction; Sodium; Sodium Chloride; Sodium-Restricted Diet; System; Testing; Tubular formation; Untranslated RNA; Urine; Water; analog; blood pressure regulation; care burden; circadian; circadian pacemaker; clinically relevant; collecting tubule structure; dietary salt; epithelial Na+ channel; high salt diet; hypertension treatment; individualized medicine; male; mortality; mouse model; novel; overexpression; peptide hormone; precision medicine; receptor; response; salt sensitive; salt sensitive hypertension; sex; side effect; treatment optimization; Address; Aldosterone; Animals; Blood Pressure; Cadherins; Cell model; Chronic Kidney Failure; Clinical; Clock protein; Data; Diet; Distal; Duct (organ) structure; Electrolyte Balance; Endothelin; Endothelin A Receptor; Endothelin Receptor; Endothelin-1; Epidemic; Equilibrium; Exhibits; Feedback; Fluid Balance; Gene Expression; Genes; Goals; Healthcare; High Prevalence; Homeostasis; Human; Hypertension; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Lead; Link; Liquid substance; Measures; Mediating; Mineralocorticoids; Modeling; Molecular; Mus; Nephrons; Physiological; Physiology; Play; Process; Regulation; Renin; Role; Signal Transduction; Sodium; Sodium Chloride; Sodium-Restricted Diet; System; Testing; Tubular formation; Untranslated RNA; Urine; Water; analog; blood pressure regulation; care burden; circadian; circadian pacemaker; clinically relevant; collecting tubule structure; dietary salt; epithelial Na+ channel; high salt diet; hypertension treatment; individualized medicine; male; mortality; mouse model; novel; overexpression; peptide hormone; precision medicine; receptor; response; salt sensitive; salt sensitive hypertension; sex; side effect; treatment optimization

Project Summary: Elevated aldosterone levels and high salt diets contribute to the epidemics of hypertension and kidney disease. This is in part due to dysregulation of fluid and electrolyte balance within the kidney. The kidney plays a key role in the regulation of blood pressure (BP) through its homeostatic control of sodium (Na) and water balance by the distal nephron. This process is tightly regulated by the mineralocorticoid aldosterone and other intrinsic regulatory mechanisms, including the endothelin-1 (ET-1) signaling axis. We identified ET-1 as a novel aldosterone target. We also demonstrated that ET-1 acts in a feedback mechanism within the kidney collecting duct to inhibit Na reabsorption via signaling through both the ETRA and ETRB receptors. This intrinsic regulatory mechanism, the renal aldosterone endothelin feedback system (RAEFS), is required for normal BP regulation and Na homeostasis. The significance of this feedback system is illustrated by the dramatic effects caused by its disruption, which causes salt-sensitive hypertension and fluid retention. Clinically, ETRA/B blockers have shown efficacy in kidney disease, but fluid retention is a troubling side effect. We have identified the circadian clock protein PER1 as a critical component for BP regulation and renal Na homeostasis. We have shown that PER1 acts in a sex-specific manner to control Na balance and BP in the setting of salt-sensitive hypertension. We demonstrated that PER1 is a negative regulator of ET-1 expression, linking PER1 and the RAEFS. Using a model of salt-sensitive hypertension, we recently discovered that male kidney-specific (KS)-PER1 KO mice exhibit increased BP and inappropriate Na retention in response to a high salt diet plus an aldosterone analog. Importantly, KS-PER1 KO mice exhibit elevated levels of ET-1 in the kidney and urine. We also recently discovered a novel, long non-coding RNA that is antisense to the ET-1 gene, EDN1-AS. EDN1-AS is a positive regulator of ET-1. Our new data show that ET-1 and EDN1-AS are positively regulated by aldosterone but negatively regulated by PER1. Together these data support our overall hypothesis that PER1 maintains BP and Na balance through inhibiting the action of aldosterone to increase ET-1 in the kidney. We propose that this modulation of the RAEFS constitutes a new paradigm for feedback control of Na balance and BP. Aim 1 will utilize whole animal BP and Na balance studies in control and kidney- specific PER1 and ET-1 KO mice. Aim 2 will employ the isolated perfused collecting duct to test the effect of PER1 on ET-1-dependent renal tubular Na reabsorption. Aim 3 will use a unique cell model of the collecting duct with inducible overexpression of EDN1-AS to determine the mechanism by which PER1, aldosterone, and EDN1-AS regulate the ET-1 gene. We propose that understanding the circadian molecular regulation of ET-1 is the key to unlocking the difficulties associated with ET-receptor blockers. Completion of these studies will provide the mechanistic knowledge necessary to determine the feasibility of employing circadian precision medicine for the tailored treatment of salt-sensitive hypertension.

项目摘要：醛固酮水平升高和高盐饮食有助于高血压的流行病 和肾脏疾病。这部分是由于肾脏中流体和电解质平衡的失调。这 肾脏通过钠（NA）的稳态控制在血压调节（BP）中起关键作用 和远端的水平。该过程受矿物皮质激素醛固酮的严格调节 以及其他固有的调节机制，包括内皮素-1（ET-1）信号轴。我们确定了ET-1 作为一种新型的醛固酮靶标。我们还证明了ET-1在反馈机制中起作用 肾脏收集导管以通过ETRA和ETRB受体的信号传导抑制Na的重吸收。这 内在的调节机制，肾醛固酮内皮素反馈系统（RAEFS）是必需的 正常的BP调节和NA稳态。此反馈系统的重要性由 由其破坏引起的戏剧性影响，这会导致盐敏感的高血压和液体保留。 在临床上，etra/b阻滞剂显示出在肾脏疾病中的功效，但液体保留是令人不安的副作用。 我们已经确定昼夜节律蛋白PER1是BP调节和肾脏NA的关键成分 稳态。我们已经表明，per1以性别特定方式起作用以控制Na平衡和BP 盐敏感高血压的设置。我们证明PER1是ET-1表达的负调节剂， 将Per1和Raefs连接起来。使用盐敏感高血压模型，我们最近发现雄性 肾脏特异性（KS）-PER1 KO小鼠表现出BP的增加和不适当的NA保留，以响应高 盐饮食加醛固酮类似物。重要的是，KS-PER1 KO小鼠在ET-1的水平升高 肾脏和尿液。我们最近还发现了一种新型的，长的非编码RNA，对ET-1反义 Gene，Edn1-As。 EDN1-AS是ET-1的积极调节剂。我们的新数据表明，ET-1和EDN1-是 受醛固酮的阳性调节，但受到PER1的负调节。这些数据共同支持我们的整体 假设PER1通过抑制醛固酮的作用来维持BP和NA平衡 ET-1在肾脏中。我们建议对RIEF的这种调制构成了一种新的反馈范式 控制NA平衡和BP。 AIM 1将利用整个动物BP和NA平衡研究在对照和肾脏中 - 特定的PER1和ET-1 KO小鼠。 AIM 2将采用孤立的灌注收集管来测试 per1在ET-1依赖性肾小管NA的重吸收上。 AIM 3将使用收集的独特单元模型 EDN1-AS的诱导过表达的导管确定PER1，醛固酮和 EDN1-AS调节ET-1基因。我们建议了解ET-1的昼夜节律调节 是解锁与ET受体阻滞剂相关的困难的关键。这些研究的完成将 提供必要的机械知识来确定使用昼夜节律的可行性 用于定制盐敏感高血压治疗的药物。