Aldosterone-Induced Hypertension is Sex-Dependent, Mediated by T Cells and Sensitive to GPER Activation.

AIMS: The G protein-coupled estrogen receptor 1 (GPER) may modulate some effects of aldosterone. Additionally, G-1 (a GPER agonist) can lower blood pressure (BP) and promote T cell-mediated anti-inflammatory responses. This study aimed to test the effects of G-1 and G-15 (a GPER antagonist) on aldosterone-induced hypertension in mice, and to examine the cellular mechanisms involved. METHODS AND RESULTS: C57Bl/6 (wild-type, WT), RAG1-deficient and GPER-deficient mice were infused with vehicle, aldosterone (0.72 mg/kg/d S.C. plus 0.9% NaCl for drinking) +/- G-1 (0.03 mg/kg/d S.C.) and/or G-15 (0.3 mg/kg/d S.C.) for 14 d. G-1 attenuated aldosterone-induced hypertension in male WT but not male GPER-deficient mice. G-15 alone did not alter hypertension but it prevented the anti-hypertensive effect of G-1. In intact female WT mice, aldosterone-induced hypertension was markedly delayed and suppressed compared with responses in males, with BP remaining unchanged until after d 7. By contrast, co-administration of aldosterone and G-15 fully increased BP within d 7 in WT females. Similarly, aldosterone robustly increased BP by d 7 in ovariectomised WT females, and in both sexes of GPER-deficient mice. Whereas aldosterone had virtually no effect on BP in RAG1-deficient mice, adoptive transfer of T cells from male WT or male GPER-deficient mice into male RAG1-deficient mice restored the pressor response to aldosterone. This pressor effect could be attenuated by G-1 in RAG1-deficient mice that were reconstituted with either WT or GPER-deficient T cells, suggesting that G-1 does not act via T cells to lower BP. CONCLUSIONS: Our findings indicate that although aldosterone-induced hypertension is largely mediated by T cells, it can be attenuated by activation of GPER on non-T cells, which accounts for the sex difference in sensitivity to the pressor effect. TRANSLATIONAL PERSPECTIVE: Up to 30% of hypertensive patients are resistant to treatment, hence, there is a vital need to develop new therapies to more effectively treat hypertension. Targeting the GPER may have therapeutic potential to treat hypertension.