T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-GammaNovelty and Significance
This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
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.
- Received December 14, 2016.
- Revision received March 7, 2017.
- Accepted March 13, 2017.
- © 2017 American Heart Association, Inc.