High Salt Activates CD11c+ Antigen Presenting Cells Via Serum Glucocorticoid Kinase 1 to Promote Renal Inflammation and Salt-Sensitive Hypertension

Salt-sensing mechanisms in hypertension involving the kidney, vasculature and central nervous system have been well studied; however, recent studies suggest that immune cells can sense sodium (Na + ). Antigen presenting cells (APCs) including dendritic cells (DCs) critically modulate inflammation by activating T cells and producing cytokines. We recently found that Na + enters DCs through amiloride-sensitive channels including the alpha and gamma subunits of the epithelial sodium channel (ENaC) 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 APCs mediates salt-induced expression and assembly of ENaCα and ENaCγ 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. CD11c + APCs 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 CD11c + cells prevented the high salt induced expression of ENaC and NADPH oxidase. These studies indicate that expression of SGK1 in CD11c + APCs contributes to the pathogenesis of salt-sensitive hypertension.