Interleukin 6 plus High Salt Increases Systolic Blood Pressure

Abstract

Cytokines and immune cells are implicated in the development of hypertension (HTN), and clinically, interleukin 6 (IL‐6) is independently correlated with HTN. HTN is also characterized by increased sodium (Na+) reabsorption along the aldosterone‐sensitive distal nephron (ASDN), as well as increased expression and/or activity of Na+ transport proteins, such as the sodium chloride cotransporter (NCC) and the epithelial sodium channel (ENaC). We have previously shown that IL‐6 can activate the mineralocorticoid receptor (MR) in vitro, and intrarenal IL‐6 perfusion significantly increases expression of total and phosphorylated (T53)‐NCC, and ENaC α/γ subunits in vivo. Here, we hypothesize that IL‐6 increases Na+ reabsorption, leading to HTN. To determine whether IL‐6 increases blood pressure (BP), mice (C57Bl6) were implanted with miniosmotic pumps and tail cuff plethysmography used to measure systolic BP during IL‐6 infusion (16 ng/hr, 0.01% BSA in saline) or sham surgery. Mice were fed normal chow (NC) or high salt (HS) food. Mice with systemic IL‐6 infusion (3 days) plus HS diet had significantly increased BP as compared to HS alone (129±6 mmHg vs. 110±5 mmHg, n=4, *p<0.05) with no increases in proteinuria (7 days). No changes in BP was observed in mice treated with IL‐6 and fed NC.To investigate whether intra‐renal IL‐6 activates NCC via the MR, in vivo, jugular catheters were attached to a miniosmotic pump and inserted under the renal capsule. Mice were infused with IL‐6 (16 ng/hr, 0.1% BSA in saline; 3 days) or vehicle. Mice were sacrificed, tissues removed and then cryosectioned for immunofluorescence (IF) studies. We observed a significant increase in phosphor(T53)‐NCC expression (291±12 mean pixel intensity, MPI) vs. vehicle (236±9; p<0.01, n=3). Mice were then given the MR antagonist (spironolactone, [0.6 mg/day] in peanut butter); we observed a significant reduction in the IL‐6‐mediated increase in phosphor(T53)‐NCC expression (210±12 MPI; p<0.001, n=3).Our data suggest that IL‐6 infusion plus HS increases systolic BP, beginning on day 3, without significant renal damage on day 7. Although we observed a significant increase in IL‐6‐mediated MR‐dependent phosphor(T53)‐NCC expression, our metabolic cage data suggest that pressure natriuresis may be occurring by day 3. Together, these data suggest a novel role for cytokines and high salt in the development of HTN.Support or Funding InformationEmory SIRE to GGH and BMW; ASPET SURF to GGH; Emory University SUPERR 5R25DK101390‐05 to HCM; NIDDK085097 and VA MERIT I01BX002322 to RSH and 2T32DK7656‐2 to BMWThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.