Abstract P214: Serum Glucocorticoid Kinase 1 and Sympathetic Nerve Activity in Salt-Sensitive Hypertension.

Abstract

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 (BP) elevation, renal injury, and cardiovascular disease remains unclear. Substantial evidence supports a role of increased sympathetic output in salt-dependent hypertension and this promotes renal inflammation and dysfunction. It has been shown that salt accumulates in the interstitium of hypertensive humans and animals and drives immune cells toward a proinflammatory phenotype through the salt sensing kinase serum/glucocorticoid kinase 1 (SGK1). We have also shown an important role of monocytes and monocyte-derived dendritic cells in hypertension. In this study, we tested the hypothesis that SGK1 in myeloid CD11c + cells promote salt-sensitive hypertension by increasing sympathetic outflow. To test this hypothesis, we created mice lacking SGK1 in CD11c + cells (SGK1 CreCD11c mice) and used SGK1 fl/fl mice as controls. To induce salt-sensitivity, mice received 0.5 mg/ml of N-Nitro-L-arginine methyl ester hydrochloride (L-NAME) in the drinking water for 2 weeks. This was followed by a 2-week washout period and then a 4% high salt diet for 3 weeks. BP was monitored using telemetry. We found that BP elevation during high salt feeding was significantly attenuated in SGK1 CreCD11c mice compared to SGK1 fl/fl mice (125 ± 1 vs. 141 ± 1 mmHg; p < 0.01). SGK1 CreCD11c mice had a significant reduction in CD45 + , CD3 + , CD4 + CD8 + and CD19 + cells in the kidney compared to SGK1 fl/fl mice as assessed by flow cytometry (p < 0.05). Interestingly, on high salt, SGK1 CreCD11c mice had a significant reduction in heart rate (HR) compared to SGK1 fl/fl mice (528 ± 2 vs. 592 ± 7 bpm; p = 0.006). Microglial cells of the brain express CD11c, and we found that the reduction in HR was associated with a marked reduction in HR variability in SGK1 CreCD11c mice compared to SGK1 fl/fl mice (1.65 ± 0.38 vs. 3.00 ± 0.57; p = 0.0018), indicating a reduction in sympathetic outflow. Our data indicate that SGK1 in CD11c + myeloid cells and likely those of the central nervous system, modulate BP and sympathetic outflow promoting the pathogenesis of salt-sensitive hypertension.