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.

项目摘要 肥胖及其不良后果是全球公共卫生问题。虽然我们已经取得了令人信服的 尽管取得了一些进展，但仍然需要更有效的控制肥胖相关疾病的战略。最近， 来自人类和动物研究的越来越多的证据表明，一种新的脂肪因子，C1 q/TNF相关蛋白， 1（CTRP 1），显示出对葡萄糖和脂质紊乱的多种有益作用。这表明潜力巨大 CTRP 1作为肥胖相关代谢紊乱的新治疗靶点。然而，潜在的 CTRP 1的高血压作用限制了其应用。因此，本提案旨在了解CTRP 1的作用 肥胖相关的高血压。肾功能异常及其相关的钠重吸收增加 作为肥胖相关高血压发展的基本机制。然而，没有研究表明 为了确定CTRP 1在调节肾钠重吸收和血压中的作用， 在肥胖期间。在初步研究中，我们发现了CTRP 1相互作用的未描述的直接调节作用， 与（原）肾素受体（PRR）在体外控制ENaC激活;这可能与Nox 4依赖性H2 O2有关 生产我们提供了进一步的证据，外源性CTRP 1输注减少尿钠排泄 和血压升高，伴有循环肾素-血管紧张素-醛固酮系统增加 （RAAS）活性。这些结果支持CTRP 1在调节钠重吸收和血液循环中的功能。 基础条件下的压力。来自临床和动物研究的新证据揭示了正相关性 血浆CTRP 1水平与体重指数或血压之间的关系。因此，我们假设CTRP 1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的作用：1） PRR依赖性ENaC激活的局部肾脏机制; 2）循环系统性ENaC激活的全身机制。 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 目的1，我们将采用多种基因打靶技术来确定CTRP 1在肾钠处理中的作用 和肥胖时的血压在目标2中，我们将剖析CTRP 1诱导的信号传导机制， PRR依赖性途径和Nox 4/H2 O2途径在控制ENaC中的协调激活， 培养细胞在目标3中，在脂肪细胞特异性CTRP 1缺失小鼠中，我们将确定脂肪细胞- 在肥胖期间循环RAAS活化中衍生的CTRP 1。此外，我们将探讨 CTRP 1直接影响肾小球体中肾素的合成或分泌 灌流小鼠肾脏模型。这一建议的新信息将大大加强我们对以下问题的了解： CTRP 1在肥胖相关高血压中作用，并导致治疗肥胖相关高血压的新疗法 疾病