T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma. Issue 10 (12th May 2017)

• Record Type: Journal Article
• Authors: Sun, Xue-Nan; Li, Chao; Liu, Yuan; Du, Lin-Juan; Zeng, Meng-Ru; Zheng, Xiao-Jun; Zhang, Wu-Chang; Liu, Yan; Zhu, Mingjiang; Kong, Deping; Zhou, Li; Lu, Limin; Shen, Zhu-Xia; Yi, Yi; Du, Lili; Qin, Mu; Liu, Xu; Hua, Zichun; Sun, Shuyang; Yin, Huiyong; Zhou, Bin; Yu, Ying; Zhang, Zhiyuan; Duan, Sheng-Zhong
• Is Part Of: Circulation research. Volume 120:Issue 10(2017)
• Publication Date: 2017-05-12
• Subjects: hypertension -- inflammation -- interferon-gamma -- mineralocorticoid receptor -- T-cell; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.310480
• Languages: English
• ISSNs: 0009-7330

Abstract

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 mouse in combination with angiotensin II–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 T-cell MR knockout mitigated angiotensin II–induced accumulation of interferon-gamma (IFN-γ)–producing T cells, particularly CD8 + population, in both kidneys and aortas. Similarly, eplerenone attenuated angiotensin II–induced elevation of BP and accumulation of IFN-γ–producing T cells in wild-type mice. In cultured CD8 + T cells, T-cell MR knockout suppressed IFN-γ expression whereas T-cell MR overexpression and aldosterone both enhanced IFN-γ expression. At the molecular level, MR interacted with NFAT1 (nuclear factor of activated T-cells 1) and activator protein-1 in T cells. Finally, T-cell MR overexpressing mice manifested more elevated BP compared with control mice after angiotensin II infusion and such difference was abolished by IFN-γ–neutralizing antibodies. Conclusions: : MR may interact with NFAT1 and activator protein-1 to control IFN-γ 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. Abstract : Supplemental Digital Content is available in the text.