Serum Glucocorticoid Kinase 1 (SGK1) Expression in Dendritic Cells Contributes to Salt‐Induced Hypertension in Mice

Abstract

Salt‐sensing mechanisms in hypertension involving the kidney have been well studied; however, recent studies suggest that immune cells can sense Na+. Antigen presenting cells like dendritic cells (DCs) critically modulate inflammation by activating T cells and producing cytokines. We recently found that sodium enters DCs through amiloride‐sensitive channels including the alpha and gamma subunits of the epithelial sodium channel (ENaCαγ) and mediates NADPH oxidase‐dependent formation of immunogenic isolevuglandin (IsoLG)‐protein adducts leading to inflammation and hypertension. Here we describe a novel pathway in which the salt sensing kinase serum/glucocorticoid kinase 1 (SGK1) in DCs mediates salt‐induced assembly of ENaCαγ and promotes salt‐sensitive hypertension by activation of the NADPH oxidase and formation of IsoLG‐protein adducts. Mice lacking SGK1 in CD11c+ cells were protected from renal inflammation, endothelial dysfunction and developed blunted hypertension during the high salt feeding phase of the N‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME)/high salt model of salt‐sensitive hypertension. DCs treated with high salt exhibited increased expression of ENaCγ which co‐immunoprecipitated with ENaCα. This was associated with increased activation and expression of various NADPH oxidase subunits. Genetic deletion or pharmacological inhibition of SGK1 in DCs prevented the high salt induced expression of ENaCγ (0.04±0.04, WT, 0.05±0.04, WT plus HS and 0.06±0.05, KO plus HS, p<0.01) and ENaCα (0.29±0.20, for WT, 0.28±0.19, for WT plus HS and 0.30±0.24, for KO plus HS, p<0.01). These results indicate that expression of SGK1 in DCs contributes to the pathogenesis of salt‐sensitive hypertension by stabilizing expression of ENaCαγ leading to activation of NADPH oxidase.Support or Funding InformationThis work was supported by the American Heart Association grants POST290900 and SFRN204200, and National Institutes of Health grants K01HL130497, R01HL125865, and R01HL039006.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.