A17004 Interleukin 6 plus High Salt Increases Systolic Blood Pressure via Mineralocorticoid Receptor-Dependent Activation of SGK1 and NCC

Abstract

Objectives: Hypertension (HTN) is characterized by increased Na+ reabsorption and systemic inflammation, such as increased cytokines. Clinically, interleukin 6 (IL-6) is independently correlated with HTN. We have previously shown that IL-6 can activate the mineralocorticoid receptor (MR) in vitro. Here, we hypothesize that IL-6 activates the MR, via IL-6 receptor alpha (IL-6R), leading to HTN. Methods: Mice were implanted with miniosmotic pumps infusing IL-6 (16 ng/hr) systemically or intra-renal via jugular catheter, or sham surgery performed. Mice were fed normal chow (NC) or high salt (HS) food. Tail cuff plethysmography was used to measure systolic blood pressure (BP). Immunofluorescence (IF) studies were performed on cryosectioned kidney tissue. Results: Systemic IL-6 infusion (3 days) plus HS diet significantly increased BP as compared to HS alone (129 ± 6 mmHg vs. 110 ± 5 mmHg ) with no increases in proteinuria (7 days). No changes in BP was observed in mice treated with IL-6 and fed NC. We observed a significant increase in phosphor (T53)-NCC expression (291 ± 12 mean pixel intensity, MPI) vs. vehicle (236 ± 9). Mice were then given the MR antagonist (spironolactone, 0.6 mg/day); we observed a significant reduction in the IL-6-mediated increase in phosphor (T53)-NCC expression (210 ± 12 MPI). SGK1 fluorescence was increased following IL-6 perfusion (306 ± 4.7 vs. 263 ± 4.4MPI); spironolactone reduced this response (224.3 ± 4.5 vs. vehicle). We observed a significant increase in basolateral gp130 expression, important for IL-6R signaling, with IL-6 infusion. Conclusion: Our data suggest that IL-6 infusion plus HS increases systolic BP, via MR dependent activation of SGK1, leading to increases in Na+ reabsorption through NCC. Together, these data suggest a novel role for cytokines and high salt in the development of HTN.