Role of CTRP1 in Renal Sodium Handling in Obesity-Related Hypertension

CTRP1 在肥胖相关高血压肾钠处理中的作用

• 批准号: 10682636
• 负责人: Fei Wang
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682636
• 关键词: Adipocytes; Adipose tissue; Affect; Aldosterone; Animals; Attenuated; Biochemistry; Blood Pressure; Body mass index; Cardiovascular Diseases; Cells; Clinical; Complement 1q; Cultured Cells; Data; Development; Essential Hypertension; Excretory function; Exhibits; Gene Targeting; Genetically Engineered Mouse; Glucose; Goals; Healthcare Systems; High Fat Diet; High Prevalence; Homeostasis; Human; Hydrogen Peroxide; Hypertension; In Vitro; Infusion procedures; Intravenous infusion procedures; Juxtaglomerular Apparatus; Kidney; Kidney Diseases; Knockout Mice; Link; Mediating; Metabolic Diseases; Modeling; Mus; Obesity; Obesity Related Hypertension; Obesity associated disease; Pathogenesis; Pathway interactions; Plasma; Play; Production; Proteins; Public Health; Publishing; Reactive Oxygen Species; Recombinants; Regional Perfusion; Regulation; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Role; Sampling; Signal Induction; Signal Transduction; Sodium; Sodium Channel; TNF gene; Techniques; Testing; Transgenic Mice; Tubular formation; absorption; adipokines; adverse outcome; blood pressure elevation; blood pressure regulation; catalase; design; epithelial Na+ channel; global health; hypertensive; hypertensive factor; in vivo; inhibitor; insight; lipid disorder; mRNA Expression; new therapeutic target; novel; novel strategies; novel therapeutics; obesity management; receptor; response; urinary

Project Summary Obesity and its adverse consequences are global public health concerns. Though we have achieved compelling advances, more effective strategies for managing obesity-associated diseases are still in high demand. Recently, accumulating evidence from human and animal studies indicate that a novel adipokine, C1q/TNF-related protein 1 (CTRP1), displays multiple beneficial effects on glucose and lipid disorders. This suggests immense potential for CTRP1 to serve as a novel therapeutic target for obesity-related metabolism disorders. However, the potential hypertensive effect of CTRP1 limits its application. Therefore, this proposal aims to understand the role of CTRP1 in obesity-related hypertension. Abnormal kidney function and its associated increases in sodium reabsorption serve as a fundamental mechanism in developing obesity-related hypertension. Nevertheless, no studies have been carried out to determine the role of CTRP1 in regulating renal sodium reabsorption and blood pressure during obesity. In preliminary studies, we discovered an undescribed direct regulatory effect of CTRP1 interaction with (pro)renin receptor (PRR) in controlling ENaC activation in vitro; this may be linked to Nox4-dependent H2O2 production. We presented further evidence that exogenous CTRP1 infusion reduced urinary sodium excretion and elevated blood pressure accompanied by increased circulating renin-angiotensin-aldosterone system (RAAS) activity in vivo. These results support the function of CTRP1 in regulating sodium reabsorption and blood pressure under basal conditions. Emerging evidence from clinical and animal studies reveal a positive correlation between plasma CTRP1 levels and body mass index or blood pressure. Thus, we hypothesize that CTRP1 plays a role in determining blood pressure during obesity via stimulating renal sodium reabsorption in two ways: 1) The local renal mechanism of PRR-dependent ENaC activation; 2) The systemic mechanism of circulating RAAS-dependent abnormal renal sodium handling. Three specific aims are designed to test this hypothesis. In Aim 1, we will employ multiple gene targeting techniques to determine the role of CTRP1 in renal sodium handling and blood pressure during obesity. In Aim 2, we will dissect CTRP1-induced signaling mechanisms involving coordinated activation of the PRR-dependent pathway and the Nox4/H2O2 pathway in controlling ENaC in cultured cells. In Aim 3, within adipocyte-specific CTRP1 deletion mice, we will identify the role of adipocyte- derived CTRP1 in circulating RAAS activation during obesity. Furthermore, we will explore the possibility of CTRP1 direct affecting renin synthesis or secretion in the juxtaglomerular apparatus by using an isolated perfused mice kidney model. New information from this proposal would greatly enhance our understanding of the role of CTRP1 in obesity-related hypertension and lead to novel therapies to manage obesity-related diseases.

项目概要 肥胖及其不良后果是全球公共卫生问题。尽管我们取得了令人瞩目的成就 尽管取得了进展，但仍然需要更有效的策略来管理与肥胖相关的疾病。最近， 人类和动物研究中不断积累的证据表明，一种新型脂肪因子 C1q/TNF 相关蛋白 1 (CTRP1)，对血糖和血脂紊乱表现出多种有益作用。这表明巨大的潜力 CTRP1 作为肥胖相关代谢紊乱的新治疗靶点。然而，潜力 CTRP1的高血压作用限制了其应用。因此，本提案旨在了解CTRP1的作用 与肥胖相关的高血压。肾功能异常及其相关的钠重吸收增加 是发展肥胖相关高血压的基本机制。尽管如此，还没有研究表明 已进行以确定 CTRP1 在调节肾钠重吸收和血压中的作用 肥胖期间。在初步研究中，我们发现了 CTRP1 相互作用的未描述的直接调节作用 与肾素原受体 (PRR) 一起控制 ENaC 体外激活；这可能与 Nox4 依赖的 H2O2 有关 生产。我们提供了进一步的证据表明外源性 CTRP1 输注减少了尿钠排泄 血压升高，伴有循环肾素-血管紧张素-醛固酮系统增加 （RAAS）体内活性。这些结果支持 CTRP1 在调节钠重吸收和血液中的功能 基础条件下的压力。临床和动物研究的新证据揭示了正相关性 血浆 CTRP1 水平与体重指数或血压之间的关系。因此，我们假设 CTRP1 发挥作用 通过两种方式刺激肾钠重吸收，在肥胖期间确定血压中发挥作用：1) PRR 依赖性 ENaC 激活的局部肾脏机制； 2）循环的系统机制 RAAS 依赖性肾钠处理异常。设计了三个具体目标来检验这一假设。在 目标1，我们将采用多种基因靶向技术来确定CTRP1在肾钠处理中的作用 和肥胖期间的血压。在目标 2 中，我们将剖析 CTRP1 诱导的信号传导机制，涉及 PRR依赖性途径和Nox4/H2O2途径的协调激活在控制ENaC中的作用 培养的细胞。在目标 3 中，在脂肪细胞特异性 CTRP1 缺失小鼠中，我们将确定脂肪细胞- 衍生的 CTRP1 在肥胖期间循环 RAAS 激活中的作用。此外，我们将探讨以下可能性： CTRP1 通过使用分离的方法直接影响肾小球旁装​​置中的肾素合成或分泌 灌注小鼠肾脏模型。该提案中的新信息将极大地增强我们对 CTRP1 在肥胖相关高血压中的作用并导致治疗肥胖相关高血压的新疗法 疾病。