Dietary High Salt Intake Exacerbates Serum Glucocorticoid-Regulated Kinase 1 (Sgk1)-Mediated T Cell Pathogenicity in L-Name/High Salt-Induced Hypertension

Abstract

Most hypertensive cases are primarily associated with modifiable risk factors like salt intake. Sodium (Na+) concentrates in tissues over time and activates different immune cell subsets, including TH17 and dendritic cells, setting the stage for hypertension development. Previous data has shown that in addition to TH17 and dendritic cells, memory T cells play a vital role in the genesis of hypertension. Memory T cells survive for prolonged periods of time and are reactivated upon repeated hypertensive stimuli. Once reactivated, memory T cells infiltrate the kidney and the vasculature, releasing inflammatory cytokines, which drive organ dysfunction. Importantly, Serum Glucocorticoid Kinase 1 (SGK1), an important intracellular sensor of Na+, was shown to be necessary for NaCl-induced activation of TH17 cells and dendritic cells. To determine whether this role for SGK1 extends to memory T cells, we tested the hypothesis that SGK1 in T cells is necessary for forming memory T cells and activating salt-sensitive hypertension, and that this process is key to the initiation and progression of kidney and vascular dysfunction. We employed mice with T cell-specific deletion of SGK1, SGK1fl/fl x tgCD4cre mice and used SGK1fl/fl mice as controls. Mice were treated with L-NAME (0.5mg/ml) in the drinking water for 2 weeks, then allowed a 2-week washout interval, followed by a 3-week high salt (HS) diet (4% NaCl). L-NAME/HS significantly increased blood pressure and memory T cell infiltration in the kidney and bone marrow of SGK1fl/fl mice, compared to SGK1fl/fl x tgCD4cre mice on L-NAME/HS or in groups on a normal diet (ND). In additional studies, we found that loss of SGK1 in T cells protects from renal and vascular inflammation and injury. SGK1fl/fl mice demonstrated increased albuminuria, renal fibrosis, and IFN-γ levels after L-NAME/HS. Myography studies demonstrated an impaired relaxation in response to acetylcholine but not sodium nitroprusside in mesenteric arterioles from SGK1fl/fl mice, but not SGK1fl/fl x tg CD4cre mice, which were protected from vascular dysfunction. Bone marrow memory T cells were adoptively transferred from SGK1fl/fl x tgCD4cre or SGK1fl/fl mice that had undergone the L-NAME/HS protocol, to normotensive recipient CD45.1 mice fed HS for 3 weeks. Radiotelemetry recording of blood pressure revealed that mice that received bone marrow TEM cells from SGK1fl/fl x tgCD4cre mice did not develop salt sensitivity and were protected from developing a hypertensive response compared to mice that received the control TEM cells from SGK1fl/fl mice. Our data provide a potential mechanism by which SGK1 promotes the formation of memory T cells, their development of salt sensitivity, and their mediation of renal and vascular dysfunction.