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

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.

The functional duality of SGK1 in the regulation of hyperglycemia

“…Glucose-stimulated insulin secretion (GSIS) is impaired in SGK1 overactive islet β cells, especially in the presence of glucocorticoids released from adrenal gland with the possible aim to quench the enduring inflammatory response, which would be much more prominent under T1D conditions ( 20 ). SGK1 was discovered to enhance the effector function of DCs and macrophages ( 14 , 66 , 67 , 68 ). At the same time, mounting evidence points to the fact that high salt concentration boosts the polarization of Th17 lineage while limiting the suppressive function of Treg cells ( 9 , 69 , 70 ).…”

“…(C) In adipose tissue, SGK1 promotes Glut1 expression and suppresses FoxO1, which leads to intensified glucose uptake and lipid synthesis. discovered to enhance the effector function of DCs and macrophages (14,66,67,68). At the same time, mounting evidence points to the fact that high salt concentration boosts the polarization of Th17 lineage while limiting the suppressive function of Treg cells (9,69,70).…”

“…Notably, SGK1 is identified as a hub molecule on which the cascade of events elicited by high salt diet (HSD) intake converges (6,7,8). As a salt-sensing molecule, SGK1 mediates high sodium chloride-triggered responses in kidney, brain, heart and various immune cell types (9,10,11,12,13,14,15,16,17). For a long period of time, dietary management and caloric restriction were generally focused on three major energy sources, carbohydrate, fat and protein, while the role of noncaloric nutrients, namely salt (sodium chloride), is less appreciated.…”

The effect of macrophage-targeted interventions on blood pressure – a systematic review and meta-analysis of preclinical studies

“…For example, when dendritic cells are triggered by in vitro sodium excess and subsequently adoptively transferred into naive mice, hypertension is aggravated 49 , with mechanisms likely involving promotion of renal oxidative stress, inflammation, and fluid retention. [50][51][52] Also, besides the macrophage depletion methods used in the studies that could be included in this review, more (and newer) methods exist and evolve rapidly. A detailed overview is given by other authors 16,47,53 and involves among others macrophage Fas-induced apoptosis and CX3CR1-DTR models.…”

The Role of Neutrophils in Hypertension

“…On the other hand, dendritic cells (DCs) are considered as critical for the AH since there is evidence showing that they participate in T H 1 and T H 17 cell activation, by taking up neoantigens and through isoketal formation after Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation [ 27 , 28 ]. Moreover, van Beusecum et al demonstrated that the specific deletion of serum glucocorticoid kinase 1 (SGK1) in DCs prevents AH, vascular dysfunction, and kidney inflammation induced by N -Nitro- l -arginine methyl ester (L-NAME) plus a high-salt diet [ 29 ]. Apparently, SGK1 may function as a sodium sensor, allowing DC activation; this effect was also observed in CD4 + lymphocytes [ 30 ].…”