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: 10322148
• 负责人: Fei Wang
• 金额: $ 9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322148
• 关键词: Address; 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; Lead; 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; Regulation; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Role; Sampling; Signal Transduction; Sodium; Sodium Channel; TNF gene; Techniques; Testing; Transgenic Mice; Tubular formation; 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.

项目总结