Aldosterone Independent Activation of the Mineralocorticoid Receptor via IL-6 and Rac1 Induces Sodium Retention and Hypertension

通过 IL-6 和 Rac1 独立激活盐皮质激素受体醛固酮可诱导钠潴留和高血压

基本信息

批准号：
10016294
负责人：
Brandi Michele Wynne
金额：
$ 16.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016294
关键词：
Affect Aldosterone Angiotensin II Animal Model Antihypertensive Agents Binding Blood Pressure Cells Cessation of life Chlorides Clinical Complex Consumption Data Dendritic Cells Dendritic cell activation Development Diet Distal Etiology Event Excision Flow Cytometry Functional disorder Generations Genetic Goals Hormones Hypertension Immune In Vitro Individual Inflammation Inflammatory Infusion procedures Interleukin-6 Kidney Knock-out Link Measurement Mediating Messenger RNA Methods Mineralocorticoid Receptor Mineralocorticoids Minority Modeling Monomeric GTP-Binding Proteins Mus Mutate NG-Nitroarginine Methyl Ester Natriuresis Nephrons Nuclear Nuclear Translocation Organ Phenotype Physiological Plasma Play Population Process Reactive Oxygen Species Receptor Activation Reporter Response Elements Risk Factors Role Serum Signal Pathway Sodium Sodium Chloride Stimulus Testing Therapeutic Time Transactivation Tubular formation Work cytokine dietary excess epithelial Na+ channel in vivo inflammatory milieu innovation protein expression response salt sensitive salt sensitive hypertension saluretic stressor thiazide urinary

项目摘要

Project Abstract The goal of this proposed project titled “Aldosterone Independent Activation of the Mineralocorticoid Receptor via IL-6 and Rac1 Induces Sodium Retention and Hypertension” is to investigate the role of renal dendritic cells (rDCs) in mediating cytokine-induced transactivation of the mineralocorticoid receptor (MR), increasing sodium (Na+) reabsorption and blood pressure (BP). Excessive Na+ reabsorption is a main cause of hypertension and end organ damage. The mechanisms mediating pathophysiological Na+ retention are unknown; however, increased inflammation and excessive activation of distal nephron Na+ transporters, the Na+ chloride cotransporter (NCC) and the epithelial Na+ channel (ENaC) play a role. However, the mechanisms linking increased inflammation and cytokines to Na+ transporter activation are yet unidentified. Following a stressor, DCs cells secrete interleukin 6 (IL-6) producing a pro-inflammatory milieu. Our preliminary data suggest that baseline blood pressure (BP) is regulated via rDCs, and the decreased systolic BP levels observed in rDC-depleted mice may be due to decreased NCC protein expression. Further, our data suggest that hypertension (HTN) increases serum IL-6 levels, while renal cortical IL-6 mRNA levels are reduced in rDC-depleted mice. Our robust in vivo data suggest that intrarenal IL-6 infusion increases phosphorylated (pT53) NCC, and total NCC, as well as ENaC expression. We also show that systemic IL-6, plus high salt (HS, 4%) increases BP after 3 days. Together, these data strongly support a role for rDC- mediating local IL-6 levels, and IL-6 increasing Na+ transporter expression and/or activity and BP. Moreover, our in vitro data demonstrates that IL-6 induces MR nuclear translocation and activation of downstream mineralocorticoid response elements (MRE), via the small GTP-ase Rac1 and reactive oxygen species (ROS) generation, and can directly activate thiazide-sensitive Na+ transport. Thus, we hypothesize that intrarenal IL-6 transactivates the MR, increasing distal tubular Na+ reabsorption via NCC and ENaC leading to hypertension. The studies in this proposal, when completed, will demonstrate that: 1) salt-sensitive HTN activates rDCs, 2) rDCs contribute to increased intrarenal IL-6 levels during salt-sensitive HTN, 3) IL-6 independently transactivates the MR and 4) rDC-mediated IL-6 secretion increases NCC and ENaC Na+ transport leading to HTN.

项目摘要该拟议项目的目标为“盐皮质激素的醛固酮独立激活” 受体通过 IL-6 和 Rac1 诱导钠潴留和高血压”旨在研究肾功能的作用树突状细胞（rDC）介导细胞因子诱导的盐皮质激素受体（MR）反式激活，钠 (Na+) 重吸收增加和血压 (BP) 过多是导致血压升高的主要原因。高血压和终末器官损伤的介导病理生理性Na+潴留的机制是未知；然而，炎症增加和远端肾单位 Na+ 转运蛋白过度激活， Na+ 氯化物协同转运蛋白 (NCC) 和上皮 Na+ 通道 (ENaC) 发挥作用，但其机制如下。炎症和细胞因子增加与 Na+ 转运蛋白激活之间的联系尚未确定。应激源后，DC 细胞会分泌白细胞介素 6 (IL-6)，产生促炎环境。初步数据表明，基线血压 (BP) 通过 rDC 进行调节，收缩压降低 rDC 耗尽的小鼠中观察到的 BP 水平可能是由于 NCC 蛋白表达减少所致。表明高血压 (HTN) 会增加血清 IL-6 水平，而肾皮质 IL-6 mRNA 水平则升高我们可靠的体内数据表明，肾内 IL-6 输注会增加。我们还显示了磷酸化 (pT53) NCC 和总 NCC 以及 ENaC 表达。加高盐（HS，4%）3 天后血压升高，这些数据有力地支持了 rDC- 的作用。介导局部 IL-6 水平，并且 IL-6 增加 Na+ 转运蛋白表达和/或活性以及血压。此外，我们的体外数据表明 IL-6 诱导 MR 核易位和激活下游盐皮质激素反应元件 (MRE)，通过小 GTP 酶 Rac1 和活性氧物种（ROS）的产生，并且可以直接激活噻嗪类敏感的Na + 运输因此，我们努力做到这一点。肾内 IL-6 反式激活 MR，通过 NCC 和 ENaC 增加远端肾小管 Na+ 重吸收，从而导致本提案中的研究完成后将证明：1）盐敏感性高血压。激活 rDC，2) rDC 在盐敏感 HTN 期间有助于增加肾内 IL-6 水平，3) IL-6 独立反式激活 MR，4) rDC 介导的 IL-6 分泌增加 NCC 和 ENaC Na+ 通往 HTN 的交通。