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

项目摘要 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信服的成就 在取得进展的同时，管理肥胖相关疾病的更有效的战略仍然很受欢迎。最近， 越来越多的人类和动物研究表明，一种新的脂肪因子C1q/肿瘤坏死因子相关蛋白 1(CTRP1)，对血糖和血脂紊乱有多种有益作用。这表明了巨大的潜力。 使CTRP1成为肥胖相关代谢紊乱的新治疗靶点。然而，潜在的 CTRP1的升压作用限制了其应用。因此，这项提案旨在了解CTRP1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 是肥胖相关高血压发病的基本机制。然而，目前还没有研究表明 已确定CTRP1在调节肾脏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CTRP1相互作用的一种未描述的直接调节效应 (Pro)肾素受体(PRR)在体外控制ENaC激活；这可能与NOX4依赖的过氧化氢有关 制作。我们提出了外源性CTRP1输注减少尿钠排泄的进一步证据 血压升高伴随循环肾素-血管紧张素-醛固酮系统增加 体内(RAAS)活性。这些结果支持了CTRP1在调节钠重吸收和血液中的作用 基本条件下的压力。来自临床和动物研究的新证据表明， 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症血压测定中的作用：1) PRR依赖的ENaC激活的局部肾脏机制；2)循环的全身机制 RAS依赖的肾脏钠处理异常。为了检验这一假说，我们设计了三个具体目标。在……里面 目的1、我们将利用多种基因打靶技术来确定CTRP1在肾脏钠处理中的作用。 以及肥胖期间的血压。在目标2中，我们将剖析CTRP1诱导的信号机制，包括 PRR依赖途径和NOX4/H_2O_2途径协同激活对ENaC的调控作用 培养的细胞。在目标3中，在脂肪细胞特异性CTRP1缺失的小鼠中，我们将确定脂肪细胞- 肥胖时循环RAAS激活中衍生的CTRP1。此外，我们将探讨是否有可能 CTRP1直接影响肾小球旁器肾素的合成或分泌 灌流小鼠肾脏模型。来自这项提案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管理肥胖相关的新疗法 疾病。

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.