Per1 and the kidney clock in hypertension

Per1 和高血压的肾钟

• 批准号: 10170331
• 负责人: Michelle L Gumz
• 金额: $ 29.17万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170331
• 关键词: Adult; Affect; Aldosterone; Alpha Rhythm; American; Blood Pressure; Blood Volume; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Chronic Kidney Failure; Circadian Dysregulation; Circadian Rhythms; Clock protein; Core Protein; Cues; Distal; Duct (organ) structure; Endothelin-1; Equilibrium; Gene Expression; Genes; Genetic; Goals; Health; Homeostasis; Hormones; Human; Hypertension; Kidney; Knock-out; Knockout Mice; Malignant Neoplasms; Mammals; Measures; Mediating; Metabolic; Mineralocorticoids; Modeling; Molecular; Myocardial Infarction; Nephrons; Nutritional; Outcome; Physiological; Physiology; Play; Process; Regulation; Regulator Genes; Renal function; Renin-Angiotensin-Aldosterone System; Research; Rest; Risk; Risk Factors; Role; SLC12A3 gene; Signal Transduction; Sleep; Sodium; Sodium Chloride; Stroke; System; Testing; Time; Tissues; Tubular formation; United States; blood pressure regulation; cardiovascular health; cardiovascular risk factor; cell type; circadian; circadian pacemaker; circadian regulation; clinically relevant; collecting tubule structure; defined contribution; design; epithelial Na+ channel; experimental study; hypertension treatment; molecular clock; mortality; mouse model; new therapeutic target; novel; peptide hormone; programs; protein function; receptor; renal damage; salt sensitive; salt sensitive hypertension; transcription factor; treatment strategy

Project Summary One-third of adult Americans are afflicted with hypertension, a principal risk factor for a number of mortalities, including cardiovascular disease and chronic kidney disease. The vast majority of hypertension remains uncontrolled, despite available therapies. There is a clear need to identify new targets for the treatment of hypertension. Increased risk for adverse cardiovascular outcomes is associated with disruption of the circadian rhythm of blood pressure (BP), particularly in the setting of hypertension. BP should decrease, or “dip”, at night when humans rest. Non-dipping hypertension is associated with negative cardiovascular outcomes such as stroke and kidney damage. Mechanisms underlying non-dipping hypertension are not understood but one candidate is the molecular circadian clock. The clock is comprised of several core transcription factors that regulate gene expression in nearly every cell type in the body. We have identified the circadian clock protein Per1 as an important regulator of gene expression in the kidney. The kidney plays a critical role in the regulation of sodium balance, blood volume, and therefore BP. Multiple sodium transporters, expressed throughout the renal nephron, contribute to these functions of the kidney. The kidney is responsive to the sodium-regulating mineralocorticoid hormone aldosterone. The sodium/chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) are expressed in the aldosterone-sensitive distal nephron and the collecting duct and are key determinants of renal sodium reabsorption and BP. Per1 is unique among the clock proteins because it is regulated by aldosterone. Per1 is also a novel regulator of NCC, ENaC and Endothelin-1 (ET-1), a peptide hormone that negatively regulates ENaC activity. We discovered that loss of Per1 affects the salt-sensitivity of BP and disrupts the circadian rhythm of BP, resulting in non-dipping hypertension. Taken together, our results suggest that Per1 may be a new therapeutic target for modulating BP and support a role for Per1 and the molecular kidney clock in the regulation of sodium balance and BP rhythms. The goal of this application is to test the hypothesis that Per1 regulates BP rhythms and sodium homeostasis through the coordinate regulation of NCC, ENaC, and ET-1 in the kidney. We have developed a novel, kidney-specific Per1 knockout mouse model to test this hypothesis. Aims 1 and 2 are designed to define the contribution of ENaC and NCC to Per1 action on renal sodium reabsorption and BP, whereas Aim 3 will define the role of ET-1 and its receptors in this regulation. Completion of these studies will, for the first time, specifically define the contribution of Per1 and the kidney clock to regulation of renal sodium handling and BP in a model of salt- sensitive hypertension. The studies proposed here have important implications for our understanding of mechanisms underlying non-dipping hypertension.

项目摘要 三分之一的美国成年人患有高血压，这是许多疾病的主要危险因素。 死亡率，包括心血管疾病和慢性肾病。绝大多数高血压 尽管有可用的治疗方法，但仍然不受控制。显然有必要确定新的目标， 治疗高血压。不良心血管结局风险增加与以下因素的干扰有关： 血压（BP）的昼夜节律，特别是在高血压的情况下。血压下降，或 “dip”，在晚上人类休息的时候。非突降型高血压与负性心血管 结果如中风和肾损伤。非突降型高血压的潜在机制不是 但一个候选者是分子生物钟。时钟由几个核心组成 在体内几乎每种细胞类型中调节基因表达的转录因子。我们已经确定了 生物钟蛋白Per 1是肾脏基因表达的重要调节因子。肾脏扮演着 在调节钠平衡、血容量和血压方面起关键作用。多种钠转运蛋白， 在整个肾肾单位中表达，有助于肾脏的这些功能。肾脏有反应 钠调节盐皮质激素醛固酮。钠/氯协同转运蛋白（NCC）和 上皮钠通道（ENaC）在醛固酮敏感的远端肾单位和 集合管和肾钠重吸收和血压的关键决定因素。Per 1在时钟中是唯一的 蛋白质，因为它是由醛固酮调节的。Per 1也是NCC、ENaC和内皮素-1的新型调节剂 ET-1是一种负调节ENaC活性的肽激素。我们发现Per 1的缺失会影响 血压的盐敏感性，并扰乱血压的昼夜节律，导致非浸渍高血压。采取 总之，我们的研究结果表明Per 1可能是调节BP的新的治疗靶点，并支持其作用。 Per 1和分子肾脏时钟在调节钠平衡和血压节律。这个目标 应用程序是测试Per 1通过调节血压节律和钠稳态的假设。 协调调节肾脏中的NCC、ENaC和ET-1。我们开发了一种新的肾脏特异性Per 1 基因敲除小鼠模型来验证这一假设。目标1和2旨在确定ENaC的贡献 和NCC到Per 1对肾钠重吸收和BP的作用，而Aim 3将定义ET-1和 它的受体参与了这一调节。这些研究的完成将首次具体界定 Per 1和肾脏时钟对盐-尿模型中肾脏钠处理和血压调节的贡献 敏感性高血压这里提出的研究对我们理解 非突降型高血压的潜在机制。

项目成果

Kidney-Specific BMAL1 Knockout is Protective in High Salt Diet-Induced Renal Inflammation.

肾脏特异性 BMAL1 敲除对高盐饮食引起的肾脏炎症具有保护作用。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Crislip,GeneR;Costello,HannahM;Juffre,Alexandria;Cheng,Kit-Yan;Wingo,CharlesS;Scindia,YogeshM;Gumz,MichelleL
• 通讯作者: Gumz,MichelleL

Circadian Rhythm, Clock Genes, and Hypertension: Recent Advances in Hypertension.

• DOI: 10.1161/hypertensionaha.121.14519
• 发表时间: 2021-11
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Costello HM;Gumz ML
• 通讯作者: Gumz ML

Clocking skin sodium.

记录皮肤钠。

• DOI: 10.1152/ajpregu.00453.2017
• 发表时间: 2018
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Gumz,MichelleL