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T Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon Gamma.

T Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon Gamma.
Author Information (click to view)

Sun XN, Li C, Liu Y, Du LJ, Zeng MR, Zheng XJ, Zhang WC, Liu Y, Zhu M, Kong D, Zhou L, Lu L, Shen ZX, Yi Y, Du L, Qin M, Liu X, Hua Z, Sun S, Yin H, Zhou B, Yu Y, Zhang Z, Duan SZ,


Sun XN, Li C, Liu Y, Du LJ, Zeng MR, Zheng XJ, Zhang WC, Liu Y, Zhu M, Kong D, Zhou L, Lu L, Shen ZX, Yi Y, Du L, Qin M, Liu X, Hua Z, Sun S, Yin H, Zhou B, Yu Y, Zhang Z, Duan SZ, (click to view)

Sun XN, Li C, Liu Y, Du LJ, Zeng MR, Zheng XJ, Zhang WC, Liu Y, Zhu M, Kong D, Zhou L, Lu L, Shen ZX, Yi Y, Du L, Qin M, Liu X, Hua Z, Sun S, Yin H, Zhou B, Yu Y, Zhang Z, Duan SZ,

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Circulation research 2017 03 15() pii CIRCRESAHA.116.310480
Abstract

Rationale: Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T cell MR in blood pressure (BP) regulation has not been elucidated. Objective: We aim to determine the role of T cell MR in BP regulation and to explore the mechanism. Methods and Results: Using T cell MR knockout (TMRKO) mouse in combination with angiotensin II (AngII)-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP, and attenuated renal and vascular damage. Flow cytometric analysis showed that TMRKO mitigated AngII-induced accumulation of interferon-gamma (IFNγ)-producing T cells, particularly CD8(+) population, in both kidneys and aortas. Similarly, eplerenone attenuated AngII-induced elevation of BP and accumulation of IFNγ-producing T cells in wild type mice. In cultured CD8(+) T cells, TMRKO suppressed IFNγ expression whereas T cell MR overexpression and aldosterone both enhanced IFNγ expression. At the molecular level, MR interacted with nuclear factor of activated T-cells 1 (NFAT1) and activator protein-1 (AP-1) in T cells. Finally, T cell MR overexpressing mice manifested more elevated BP compared to control mice after AngII infusion and such difference was abolished by IFNγ-neutralizing antibodies. Conclusions: MR may interact with NFAT1 and AP-1 to control IFNγ in T cells, and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.

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