Role of dendritic cell serum/glucocorticoid regulated kinase 1 in hypertension
Authors: Foss Jason D. , Barbaro Natalia R. , Xiao Liang , Harrison David G. , Kirabo Annet 
Published: November 2023

Hypertension is a major risk for death, yet the causes are largely unknown. We have previously shown that renal and vascular inflammation contribute to the development of hypertension and that NADPH oxidase‐dependent formation of immunogenic isolevuglandin (IsoLG)‐protein adducts in dendritic cells (DCs) plays an important role in this hypertensive inflammation. In addition, dietary salt intake is a well‐known risk factor for hypertension. Moreover, it has been shown that salt often accumulates in the interstitium of hypertensive humans and animals, and such high salt concentrations drive immune cells toward a proinflammatory phenotype through the salt sensing kinase serum/glucocorticoid regulated kinase 1 (SGK1). In the current study, we tested the hypothesis that activation of SGK1 by hypertensive stimuli, such as salt and angiotensin II, drive DCs to form IsoLG‐protein adducts and promote hypertension. To determine the effects of salt on DCs, mouse splenocytes were cultured in media with either normal salt (NS, 150 mM NaCl), high salt (HS, 190 mM NaCl) or HS plus an SGK1 inhibitor for 24 hours. Using flow cytometry, we found that compared to NS, HS caused a marked increase in IsoLG‐protein adduct formation in DCs. This effect was prevented by inhibition of SGK1. Western blots of protein extracts from DCs indicated that all NADPH subunits were increased by exposure of cells to HS, and that these effects were prevented by inhibition of SGK1. To determine whether these salt‐activated DCs promote hypertension, mice received adoptive transfer of splenic DCs that were cultured for 24 hours in either NS (n = 6); HS (n = 5); HS plus an SGK1 inhibitor (n = 5) or HS plus an IsoLG scavenger (n = 6). Mice were then implanted with radiotelemeters to measure mean arterial pressure (MAP) and infused with a subpressor dose (140 ng/kg/min) of angiotensin II (AngII) for two weeks. This caused no increase in MAP in mice that received NS DCs (+0.8 ± 3.3 mmHg), whereas MAP increased significantly with AngII infusion in mice that received HS DCs (+13.4 ± 5 mmHg). This pro‐hypertensive effect of salt on DCs was attenuated by inhibition of SGK1 (+3.1 ± 4.1 mmHg) and scavenging of IsoLGs (‐3.3 ± 4.4 mmHg) during salt exposure. In addition to salt, SGK1 can be activated indirectly by AngII through aldosterone signaling. To test whether SGK1 in DCs plays a role in AngII‐induced hypertension, we created mice with specific deletion of SGK1 in DCs (KO; SGK1fl/fl, CD11ccre mice) and used SGK1fl/fl mice as controls. DCs from these mice are protected from the HS‐induced activation of the NADPH oxidase. Moreover, preliminary data show that MAP after 4 weeks of AngII infusion (490 ng/kg/min) was markedly lower in KO mice (124.2 ± 7 mmHg) compared to control mice (135.8 ± 1.1 mmHg). Taken together, our data indicate that DCs can be activated by exposure to a high salt environment which often exists in hypertension, and that this likely involves NADPH oxidase‐dependent formation of IsoLG‐protein adducts. Moreover, high salt exposure can cause DCs to become pro‐hypertensive. Lastly, SGK1 in DCs may be important in the pathogenesis of AngII‐induced hypertension. These studies define a novel role of DC SGK1 in both salt‐dependent and salt‐independent hypertension.