Abstract 593: Vascular Inflammation and Hypertension are Attenuated with T Cell Deletion of Serum and Glucocorticoid-regulated Kinase 1 (SGK1)

Abstract

We have previously shown that the T cell-derived pro-inflammatory cytokine, interleukin 17A (IL-17A), is upregulated by and promotes angiotensin II-induced hypertension and contributes to vascular dysfunction. It was recently demonstrated that an excess of 40 mM of sodium chloride in culture enhances IL-17A production from CD4+ T cells in a Serum and Glucocorticoid-Regulated Kinase 1 (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 IL-17A (4.7 fold, p=0.0003) and the salt-sensing kinase SGK1 (2.2 fold, p=.001) in naive CD8+ T cells cultured under Th17 polarizing conditions. Since dietary salt intake is associated with hypertension, we hypothesized that T cell SGK1 promotes hypertension and contributes to vascular dysfunction. To test this hypothesis, we crossed SGK1 fl/fl mice with CD4cre mice to delete SGK1 in most T lymphocytes. Loss of T cell SGK1 resulted in a blunted blood pressure response to angiotensin II infusion (24.8 mmHg reduction, p=0.01) and DOCA-salt treatment (15.51 mmHg reduction, p<0.05). Moreover, vascular inflammation in response to angiotensin II infusion and/or DOCA-salt treatment was abrogated in these mice compared to SGK1 fl/fl control mice. 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). DOCA-salt induction increased total (CD45+) leukocytes in the aorta in SGK1 fl/fl mice from 7.4 to 20.6x10 3 (p<0.05) compared to no increase in mice with T cell deletion of SGK1 (8.7 to 10.8x10 3 , p=ns). Furthermore, preliminary data show that angiotensin II infusion impairs vascular relaxation in mesenteric arteries isolated from SGK1 fl/fl control mice, while this effect is blunted in angiotensin II treated mice with T cell deletion of SGK1. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and its associated vascular dysfunction.