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: 10505844
• 负责人: Brandi Michele Wynne
• 金额: $ 5.4万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505844
• 关键词: Aldosterone; Blood Pressure; Cells; Chlorides; Data; Dendritic Cells; Distal; Generations; Goals; Hypertension; In Vitro; Inflammation; Infusion procedures; Interleukin-6; Kidney; Link; Mediating; Messenger RNA; Mineralocorticoid Receptor; Mineralocorticoids; Monomeric GTP-Binding Proteins; Mus; NG-Nitroarginine Methyl Ester; Nephrons; Nuclear Translocation; Organ; Play; Reactive Oxygen Species; Receptor Activation; Response Elements; Role; Serum; Sodium; Sodium Chloride; Therapeutic; Transactivation; Tubular formation; Work; blood pressure elevation; cytokine; epithelial Na+ channel; in vivo; inflammatory milieu; protein expression; salt sensitive; salt sensitive hypertension; stressor; thiazide

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， 增加钠 (Na+) 重吸收和血压 (BP)。 Na+重吸收过多是导致Na+重吸收的主要原因 高血压和终末器官损伤。介导病理生理 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（Na+）过度激活 氯协同转运蛋白 (NCC) 和上皮 Na+ 通道 (ENaC) 发挥作用。然而，这些机制 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。我们的 初步数据表明，基线血压 (BP) 通过 rDC 进行调节，收缩压降低 在 rDC 耗尽的小鼠中观察到的水平可能是由于 NCC 蛋白表达减少所致。此外，我们的数据 表明高血压 (HTN) 会增加血清 IL-6 水平，而肾皮质 IL-6 mRNA 水平会降低 在 rDC 耗尽的小鼠中。我们可靠的体内数据表明，肾内 IL-6 输注会增加磷酸化 (pT53) NCC 和总 NCC，以及 ENaC 表达。我们还表明，全身性 IL-6 加上高盐 (HS、 4%）3天后血压升高。总之，这些数据强烈支持 rDC 介导局部 IL-6 水平的作用， 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 核转位和激活 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，我们假设 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 高血压。本提案中的研究完成后将证明：1）盐敏感 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，4) rDC 介导的 IL-6 分泌增加 NCC 和 ENaC Na+ 通往 HTN 的交通。