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

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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.