Xue-Nan Sun1, Chao Li1, Yuan Liu1, Lin-Juan Du1, Meng-Ru Zeng1, Xiao-Jun Zheng1, Wu-Chang Zhang1, Yan Liu1, Mingjiang Zhu1, Deping Kong1, Li Zhou1, Limin Lu1, Zhu-Xia Shen1, Yi Yi1, Lili Du1, Mu Qin1, Xu Liu1, Zichun Hua1, Shuyang Sun1, Huiyong Yin1, Bin Zhou1, Ying Yu1, Zhiyuan Zhang1, Sheng-Zhong Duan2. 1. From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology (X.-N.S., C.L., Y.L., L.-J.D., M.-R.Z., X.-J.Z., W.-C.Z., Y.L., S.-Z.D.), Shanghai Key Laboratory of Stomatology (X.-N.S., C.L., Y.L., L.-J.D., M.-R.Z., X.-J.Z., W.-C.Z., Y.L., S.S., Z.Z., S.-Z.D.), Department of Cardiology, Shanghai Chest Hospital (Y.Y., L.D., M.Q., X.L.), and Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital (S.S., Z.Z.), Shanghai Jiao Tong University School of Medicine, China; Institute for Nutritional Sciences (X.-N.S., C.L., Y.L., L.-J.D., M.-R.Z., X.-J.Z., W.-C.Z., M.Z., D.K., Z.-X.S., H.Y., Y.Y.) and Institute of Biochemistry and Cell Biology (B.Z.), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, China; Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China (L.Z., L.L.); Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Fudan University, China (Z.-X.S.); The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Jiangsu, China (Z.H.); and Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China (Y.Y.). 2. From the Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology (X.-N.S., C.L., Y.L., L.-J.D., M.-R.Z., X.-J.Z., W.-C.Z., Y.L., S.-Z.D.), Shanghai Key Laboratory of Stomatology (X.-N.S., C.L., Y.L., L.-J.D., M.-R.Z., X.-J.Z., W.-C.Z., Y.L., S.S., Z.Z., S.-Z.D.), Department of Cardiology, Shanghai Chest Hospital (Y.Y., L.D., M.Q., X.L.), and Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital (S.S., Z.Z.), Shanghai Jiao Tong University School of Medicine, China; Institute for Nutritional Sciences (X.-N.S., C.L., Y.L., L.-J.D., M.-R.Z., X.-J.Z., W.-C.Z., M.Z., D.K., Z.-X.S., H.Y., Y.Y.) and Institute of Biochemistry and Cell Biology (B.Z.), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, China; Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China (L.Z., L.L.); Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Fudan University, China (Z.-X.S.); The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Jiangsu, China (Z.H.); and Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China (Y.Y.). duansz@shsmu.edu.cn.
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.
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 hypertensivemouse 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.
Authors: Yi Wen; Nathan P Rudemiller; Jiandong Zhang; Xiaohan Lu; Jiafa Ren; Jamie R Privratsky; Robert Griffiths; Junyi J Zhang; Gianna E Hammer; Steven D Crowley Journal: Hypertension Date: 2020-01-27 Impact factor: 10.190
Authors: Ryan M Downey; Masaki Mizuno; Jere H Mitchell; Wanpen Vongpatanasin; Scott A Smith Journal: Am J Physiol Heart Circ Physiol Date: 2017-07-21 Impact factor: 4.733
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312