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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

基本信息

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
项目类别：
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

项目摘要

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导致高血压流行和肾脏疾病。这在一定程度上是由于肾脏内液体和电解质平衡失调。这个肾脏通过对钠的稳态控制在血压调节中起着关键作用。远端肾单位的水平衡。这一过程受到盐皮质激素醛固酮的严格调控。以及其他内在调节机制，包括内皮素-1(ET-1)信号轴。我们鉴定出ET-1 作为一种新型的醛固酮靶标。我们还证明了ET-1在体内的反馈机制中起作用肾脏集合管通过ETRA和ETRB受体的信号通路抑制钠的重吸收。这其内在的调节机制，即肾脏的醛固酮-内皮素反馈系统(RAEFS)，是正常的血压调节和钠稳态。这个反馈系统的意义由以下几个方面来说明它的破坏会造成巨大的影响，导致盐敏感型高血压和液体滞留。临床上，ETRA/B受体阻滞剂已显示出对肾脏疾病的疗效，但液体滞留是一个令人担忧的副作用。我们发现昼夜节律时钟蛋白PER1是血压调节和肾脏钠离子的关键成分动态平衡。我们已经证明，PER1以一种性别特异性的方式控制钠平衡和血压。设置盐敏感型高血压。我们证明PER1是ET-1表达的负调控因子，链接PER1和RAEFS。使用盐敏感型高血压模型，我们最近发现男性肾脏特异性(KS)-PER1 KO小鼠表现出血压升高和不适当的钠滞留盐饮食加一种醛固酮类似物。重要的是，KS-PER1 KO小鼠体内ET-1水平升高。肾脏和尿液。我们最近还发现了一种与ET-1反义的新型非编码RNA 基因，EDN1-AS。EDN1-AS是ET-1的正性调节因子。我们的新数据显示，ET-1和EDN1-AS是受醛固酮正向调节，受PER1负向调节。这些数据加在一起支持我们的总体 PER1通过抑制醛固酮升高维持血压和钠平衡的假说肾组织中的ET-1。我们认为，RAEFS的这种调制构成了一种新的反馈范式钠平衡和血压的控制。目标1将在对照和肾脏中利用整个动物的血压和钠平衡研究。特异性PER1和ET-1 KO小鼠。目的2将采用隔离灌流集合管的方法来测试 PER1对ET-1依赖的肾小管钠重吸收的影响。目标3将使用收集的独特细胞模型可诱导EDN1-AS过表达的导管，以确定PER1、醛固酮和 EDN1-AS调控ET-1基因。我们建议了解ET-1的昼夜节律分子调控是解锁与ET受体阻滞剂相关的困难的关键。完成这些研究后，提供必要的机械知识以确定采用昼夜节律精确度的可行性盐敏感型高血压的个体化治疗药物。