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: 10669391
• 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/10669391
• 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 这个拟议的项目的目标是“矿物皮质激素的独立激活 通过IL-6和RAC1受体诱导钠的保留和高血压”是为了研究肾脏的作用 树突状细胞（RDC）在介导细胞因子诱导的矿物皮质激素受体（MR），，，，， 增加钠（Na+）重吸收和血压（BP）。过量Na+重吸收是 高血压和最终器官损伤。介导病理生理NA+保留的机制是 未知;然而，远端肾脏Na+转运蛋白的感染和过量激活增加， Na+氯化物共转运蛋白（NCC）和上皮Na+通道（ENAC）起作用。但是，机制 将增加的感染和细胞因子与Na+转运蛋白激活联系起来尚不确定。 在压力源之后，DCS细胞秘密白介素6（IL-6）产生促炎的环境。我们的 初步数据表明，基线血压（BP）通过RDC调节，并且收缩期减少 在耗尽RDC的小鼠中观察到的BP水平可能是由于NCC蛋白表达降低。此外，我们的数据 表明高血压（HTN）增加了血清IL-6水平，而肾皮质IL-6 mRNA水平为 减少了RDC缺失的小鼠。我们强大的体内数据表明，肾内IL-6输注增加 磷酸化（PT53）NCC和总NCC以及ENAC表达。我们还表明系统性IL-6， 加上高盐（HS，4％）在3天后增加BP。这些数据共同支持RDC-的作用 介导局部IL-6水平，IL-6增加Na+转运蛋白表达和/或活性和BP。 此外，我们的体外数据表明IL-6影响MR核易位和激活 通过小的GTP-ase Rac1和活性氧的下游矿物皮质反应元件（MRE） 物种（ROS）的产生，可以直接激活硫嗪敏感的Na+转运。那我们假设 肾内IL-6对MR进行反式激活，通过NCC和ENAC增加远端管状Na+重吸收，导致 高血压。该提案中的研究（完成后）将证明：1）盐敏感的HTN 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和4）RDC介导的IL-6分泌增加NCC和ENAC NA+ 通往HTN的运输。

项目成果

Highlights from the International Society of Hypertension's New Investigators Network during 2019.

• DOI: 10.1097/hjh.0000000000002365
• 发表时间: 2020-05
• 期刊: Journal of hypertension
• 影响因子: 4.9
• 作者: Kruger R;Brunström M;Burger D;Charchar F;Climie R;Mirabito Colafella KM;Kempny P;Korostovtseva L;Marques FZ;Picone D;Romero C;Steckelings UM;Velkoska E;Wainford R;Wynne BM;Zanuzzi MG
• 通讯作者: Zanuzzi MG