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

• 批准号: 10478090
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478090
• 关键词: Affect; Aldosterone; Angiotensin II; Animal Model; Binding; Blood Pressure; Cells; Cessation of life; Chlorides; Clinical; Complex; Consumption; Data; Dendritic Cells; Dendritic cell activation; Development; Distal; Etiology; Event; Excision; Flow Cytometry; Functional disorder; Generations; Genetic; Goals; Hormones; Hypertension; Hypotensives; 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; Persons; 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; antagonist; blood pressure elevation; cytokine; dietary; dietary excess; epithelial Na+ channel; hypertensive; in vivo; inflammatory milieu; innovation; protein expression; response; salt sensitive; salt sensitive hypertension; saluretic; stressor; thiazide; urinary

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 这个被提议的项目的目标是“矿质皮质激素的醛固酮独立激活” 受体通过IL-6和rac1诱导钠离子滞留和高血压“是为了研究肾脏的作用 树突状细胞(RDC)在细胞因子诱导的盐皮质激素受体(MR)反式激活中的作用 增加钠(Na+)重吸收和血压(BP)。过多的Na+重吸收是导致 高血压和终末器官损伤。介导病理生理性钠离子滞留的机制有 未知；然而，炎症增加和远端肾单位Na+转运体的过度激活， Na+氯协同转运体(NCC)和上皮性Na+通道(ENaC)起作用。然而，这些机制 炎症和细胞因子增加与Na+转运体激活之间的联系尚不清楚。 在应激源作用下，DC细胞分泌白介素6(IL-6)，产生促炎环境。我们的 初步数据表明，基线血压(BP)是通过RDC调节的，而收缩压下降 在RDC耗竭的小鼠中观察到的BP水平可能是由于NCC蛋白表达减少所致。此外，我们的数据 提示高血压(HTN)会增加血清IL-6水平，而肾皮质IL-6mRNA水平 在RDC耗竭的小鼠中减少。我们强有力的体内数据表明，肾内IL-6输注增加 磷酸化(PT53)NCC和总NCC，以及ENaC的表达。我们还表明，系统性IL-6， 加高盐(HS，4%)，3天后血压升高。总之，这些数据有力地支持了RDC的作用- 调节局部IL-6水平，IL-6增加Na+转运体表达和/或活性及血压。 此外，我们的体外数据表明，IL-6诱导MR核移位和激活 下游的盐皮质激素反应元件(MRE)，通过小的GTP-ase rac1和活性氧 物种(ROS)的产生，并能直接激活对噻嗪敏感的Na+转运。因此，我们假设 肾内IL-6反式激活MR，通过NCC和ENaC增加远端肾小管对Na+的重吸收，导致 高血压。本提案中的研究完成后，将证明：1)盐敏性HTN 激活RDC，2)RDC参与盐敏感型HTN时肾内IL-6水平升高，3)IL-6 独立反式激活MR和4)RDC介导的IL-6分泌增加NCC和ENaC Na+ 通往HTN的交通工具。