High Salt Activates CD11c+ Antigen-Presenting Cells via SGK (Serum Glucocorticoid Kinase) 1 to Promote Renal Inflammation and Salt-Sensitive Hypertension. Issue 3 (September 2019)

• Record Type: Journal Article
• Authors: Van Beusecum, Justin P.; Barbaro, Natalia R.; McDowell, Zoe; Aden, Luul A.; Xiao, Liang; Pandey, Arvind K.; Itani, Hana A.; Himmel, Lauren E.; Harrison, David G.; Kirabo, Annet
• Is Part Of: Hypertension. Volume 74:Issue 3(2019)
• Publication Date: 2019-09
• Subjects: cytokines -- dendritic cells -- inflammation -- kidney; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.119.12761
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : 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 critically modulate inflammation by activating T cells and producing cytokines. We recently found that Na + enters dendritic cells through amiloride-sensitive channels including the α and γ subunits of the epithelial sodium channel (ENaC) and mediates nicotinamide adenine dinucleotide phosphate oxidase-dependent formation of immunogenic IsoLG (isolevuglandin)-protein adducts leading to inflammation and hypertension. Here, we describe a novel pathway in which the salt-sensing kinase SGK1 (serum/glucocorticoid kinase 1) in APCs mediates salt-induced expression and assembly of ENaC-α and ENaC-γ and promotes salt-sensitive hypertension by activation of the nicotinamide adenine dinucleotide phosphate 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/high salt model of salt-sensitive hypertension. CD11c + APCs treated with high salt exhibited increased expression of ENaC-γ which coimmunoprecipitated with ENaC-α. This was associated with increased activation and expression of various nicotinamide adenine dinucleotide phosphate oxidase subunits. Genetic deletion or pharmacological inhibition of SGK1 in CD11c + cells prevented the high salt-induced expression of ENaC and nicotinamide adenine dinucleotide phosphate oxidase. These studies indicate that expression of SGK1 in CD11c + APCs contributes to the pathogenesis of salt-sensitive hypertension. Abstract : Supplemental Digital Content is available in the text.