Differences and the impact of G protein-coupled estrogen receptor deletion in the vascular and renal response to aldosterone

We recently showed that the G protein-coupled estrogen receptor (GPER) protects female mice from arterial stiffening, an independent predictor of cardiovascular mortality. Previous work indicates that GPER may directly bind aldosterone and/or dimerize with the mineralocorticoid receptor. Therefore, we hypothesized that GPER may promote aldosterone-induced renal and vascular effects, particularly in male animals where less estrogen is available to activate GPER. Male (M) and female (F) wildtype (wt) and global GPER knockout (ko) mice were used between 6-7 months of age. Aldosterone was delivered to all mice subcutaneously via osmotic mini pumps at a dose of 600 μg/kg/day and drinking water was replaced with saline for 28 days. At the end of the study, tail-cuff systolic blood pressure (SBP) and metabolic cage data were collected. Data were analyzed by 2-way ANOVA followed by Sidak’s test and correlation analysis. In basal conditions, GPER ko increased systolic SBP in males but not females. After aldosterone-salt treatment, SBP was similar in Mwt versus Mko but was significantly higher in Fko versus Fwt (Pinteraction=0.002; 148 ± 12 vs. 108 ± 2 mmHg; P<0.001). Similarly, proteinuria was similar in males but greater in Fko than Fwt (Pinteraction=0.01; 6.0 ± 1.5 vs. 2.4 ± 0.4 mg/day; P=0.04), indicating greater kidney injury. In summary, GPER deletion in females revealed enhanced blood pressure and renal damage in response to an aldosterone-salt challenge. These findings do not support a role for GPER in promoting the impact of aldosterone on vascular and renal damage in either sex. In contrast, GPER protected female mice from the negative impact of aldosterone-salt on blood pressure and kidney function. More studies are needed to understand the interactions of GPER and aldosterone in the kidney of both males and females. This work was supported by the National Institutes of Health (HL133619 and AG071746 to SL, HL155841 to BO) and the American Heart Association (BV and IK) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.