Abstract 140: Deficiency of Serum Glucocorticoid Kinase 1 (SGK1) in T Lymphocytes Blunts Hypertension and Abrogates Renal/Vascular Inflammation

Abstract

We have previously shown that the T cell-derived pro-inflammatory cytokine, interleukin 17A (IL17A), is upregulated by and promotes angiotensin II-induced hypertension and contributes to renal and vascular dysfunction. It was recently demonstrated that an excess of 40 mM of sodium chloride enhances IL17A production from CD4+ T cells in an SGK1 dependent manner. We confirmed the effect of salt on CD4+ T cell differentiation and extended this finding to CD8+ T cells in which 40mM of excess salt increased the expression of IL17A (4.7 fold, p=0.0003), TonEBP (2.3 fold, p=0.002), and the salt-sensing kinase SGK1 (2.2 fold, p=0.001) in naive CD8+ cells cultured under Th17 polarizing conditions. As dietary salt intake is linked to hypertension, we hypothesized that T cell SGK1 is essential to the ability of T cells to mediate hypertension. To test this hypothesis, we crossed SGK1 fl/fl mice with CD4cre mice to delete SGK1 in T lymphocytes. Interestingly, loss of T cell SGK1 resulted in a blunted blood pressure response to angiotensin II infusion (by 31.25 mmHg, p=0.01). Moreover, angiotensin II-induced renal and vascular inflammation was abolished in these mice compared to SGK1 fl/fl control mice. Angiotensin II infusion increased total (CD45+) leukocytes in the kidney from 55.4 to 120.4x10 3 (p<0.01) in SGK1 fl/fl mice while there was no increase in mice with T cell deletion of SGK1 (48.1 to 47.5x10 3 , p=ns). Similarly, angiotensin II increased total (CD45+) leukocytes in the aorta from 5.7 to 52.4x10 3 (p<0.01) in SGK1 fl/fl mice compared to no increase in mice with T cell deletion of SGK1 (16.1 to 10.1x10 3 , p=ns). Further characterization of these mice will lead to a more thorough understanding of how T cells sense salt and promote hypertension. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and the associated end-organ inflammation.