T Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon Gamma

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.
- Mineralocorticoid receptor
- CD8+T cells
- IFNγ
- hypertension
- immune system
- nuclear receptor
- target organ damage
- Received December 14, 2016.
- Revision received March 7, 2017.
- Accepted March 13, 2017.
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- T Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon GammaXue Nan Sun, Chao Li, Yuan Liu, Lin-Juan Du, Meng-Ru Zeng, Xiao Jun Zheng, Wu Chang Zhang, Yan Liu, Mingjiang Zhu, Deping Kong, Li Zhou, Limin Lu, Zhu-Xia Shen, Yi Yi, Lili Du, Mu Qin, Xu Liu, Zichun Hua, Shuyang Sun, Huiyong Yin, Bin Zhou, Ying Yu, Zhiyuan Zhang and Sheng-Zhong DuanCirculation Research. 2017;CIRCRESAHA.116.310480, originally published March 15, 2017https://doi.org/10.1161/CIRCRESAHA.116.310480
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- T Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon GammaXue Nan Sun, Chao Li, Yuan Liu, Lin-Juan Du, Meng-Ru Zeng, Xiao Jun Zheng, Wu Chang Zhang, Yan Liu, Mingjiang Zhu, Deping Kong, Li Zhou, Limin Lu, Zhu-Xia Shen, Yi Yi, Lili Du, Mu Qin, Xu Liu, Zichun Hua, Shuyang Sun, Huiyong Yin, Bin Zhou, Ying Yu, Zhiyuan Zhang and Sheng-Zhong DuanCirculation Research. 2017;CIRCRESAHA.116.310480, originally published March 15, 2017https://doi.org/10.1161/CIRCRESAHA.116.310480