{'fraction_non_alphanumeric': 0.0302537410540013, 'fraction_numerical': 0.017241379310344827, 'mean_word_length': 5.224696356275303, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The Role of Salt, Serum Glucocorticoid Kinase 1, and NADPH Oxidase in Salt‐Sensitive Hypertension

Hypertension is a major modifiable risk for death and cardiovascular disease, yet its causes are largely unknown. Salt‐sensitive hypertension affects nearly 50% of the population and reducing salt intake decreases blood pressure and cardiovascular events in the general population. The precise mechanism of how dietary salt contributes to blood pressure elevation and cardiovascular disease remains unclear. We have previously shown that renal and vascular inflammation contributes 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. Moreover, it has been shown that salt often accumulates in the interstitium of hypertensive humans and animals, and that such high salt concentrations drive immune cells toward a proinflammatory phenotype through the salt sensing kinase serum/glucocorticoid kinase 1 (SGK1). In the current study, we tested the hypothesis that activation of SGK1 by salt drives NADPH oxidase activation and promotes hypertension. To determine the effects of salt on DCs, mouse splenocytes were cultured in either normal salt (NS, 150 mM NaCl), high salt (HS, 190 mM NaCl), or HS + SGK1 inhibitor for 24 hours. Western blot of protein extracts from DCs indicated a striking increase in all NADPH oxidase subunits by exposure to HS and that these effects were prevented by inhibition of SGK1. To test whether SGK1 in DCs plays a role in N‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME)/HS feeding, a model of salt‐sensitive hypertension, we created mice lacking SGK1 in CD11c+ cells (SGK1CreCD11c mice) and used SGK1fl/fl mice as controls. Mice were implanted with radiotelemeters to measure mean arterial pressure (MAP) and 10 days later placed on L‐NAME/HS feeding protocol. Briefly, mice are treated with L‐NAME (0.5 mg/ml) in the drinking water for two weeks. Mice received normal drinking water for 2 weeks, and were finally placed on a 4% HS diet for 3 weeks. Our preliminary data show that the % change in MAP after L‐NAME/HS feeding was significantly attenuated in SGK1CreCD11c mice compared to the SGK1fl/fl mice (115.7 ± 3.5 vs 135.4). Using flow cytometry, we assessed the effects of genetic deletion of SGK1 in DCs on vascular and renal inflammation. Preliminary data show that SGK1CreCD11c had a trend for a reduction in both aortic and renal inflammation compare to SGK1fl/fl, indicating a critical role pro‐inflammatory role for SGK1 in DCs during salt‐sensitive hypertension. Taken together, our data indicate that DCs can activated by exposure to a high salt environment which often exists in hypertension, and that this likely involves NADPH oxidase‐dependent formation of superoxide. Moreover, SGK1 in DCs may be important in the development and pathogenesis of salt‐sensitive hypertension. These studies define a novel role of SGK1 in DCs in salt‐sensitive hypertension.