T cell deletion of Serum and Glucocorticoid‐Regulated Kinase 1 (SGK1) Attenuates Hypertension and End‐Organ 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=.001) in naive CD8+ 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 end‐organ dysfunction. To test this hypothesis, we crossed SGK1fl/fl mice with CD4cre mice to delete SGK1 in 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, renal and vascular inflammation in response to angiotensin II infusion and/or DOCA‐salt treatment were abrogated in these mice compared to SGK1fl/fl control mice. Angiotensin II infusion increased total (CD45+) leukocytes in the kidney from 55.4 to 120.4 x103 (p<0.01) in SGK1fl/fl mice while there was no increase in mice with T cell deletion of SGK1 (48.1 to 47.5×103, p=ns). Similarly, angiotensin II increased total (CD45+) leukocytes in the aorta from 5.7 to 52.4×103 (p<0.01) in SGK1fl/fl mice compared to no increase in mice with T cell deletion of SGK1 (16.1 to 10.1×103, p=ns). DOCA‐salt induction increased total (CD45+) leukocytes in the aorta in SGK1fl/fl mice from 7.4 to 20.6×103 (p<0.05) compared to no increase in mice with T cell deletion of SGK1 (8.7 to 10.8×103, p=ns). Furthermore, vascular reactivity studies demonstrated that vessels from mice with T cell deletion of SGK1 were protected from angiotensin II induced endothelial dysfunction. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and the associated end‐organ inflammation.