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

项目摘要 本项目的目标是“醛固酮独立激活盐皮质激素 受体通过IL-6和Rac 1诱导钠潴留和高血压”是为了研究肾脏的作用， 树突状细胞（rDC）介导烟碱诱导的盐皮质激素受体（MR）的反式激活， 增加钠（Na+）重吸收和血压（BP）。过量的Na+重吸收是导致 高血压和终末器官损害。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+转运蛋白过度活化，Na+转运蛋白 氯协同转运蛋白（NCC）和上皮Na+通道（ENaC）发挥作用。然而，机制 将增加的炎症和细胞因子与Na+转运蛋白活化联系起来还没有确定。 在应激物之后，DC细胞分泌白细胞介素6（IL-6），产生促炎环境。我们 初步数据表明，基线血压（BP）是通过rDC调节的， 在rDC耗尽的小鼠中观察到的水平可能是由于NCC蛋白表达降低。此外，我们的数据 提示高血压（HTN）升高血清IL-6水平，而肾皮质IL-6 mRNA水平降低 在rDC缺失的小鼠中。我们的体内实验数据表明，肾内IL-6输注增加了磷酸化IL-6的表达。 （pT 53）NCC和总NCC以及ENaC表达。我们还表明，全身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介导的局部IL-6水平的作用， 和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Rac 1和活性氧 物种（ROS）的产生，并可以直接激活噻嗪敏感的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Na+重吸收，导致 高血压本提案中的研究完成后，将证明：1）盐敏HTN 激活rDC，2）rDC有助于盐敏感性HTN期间肾内IL-6水平的增加，3）IL-6 rDC介导的IL-6分泌增加NCC和ENaC Na+ 运输到HTN。

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.