Biological sex modifies aldosterone's secretion at a cellular level.

Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues' levels. This study's goal was to determine whether ALDO's biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO's biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG's MR (thereby activating the ultrashort feedback loop) reduced CYP11B2's activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO's biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO's circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.

Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses.

Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/-) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/- mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/- mice had normal ALDO levels but lacked normal renovascular responses. In humans, ERAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels.