Female Balb/C Mice Develop Salt‐sensitive Hypertension and Endothelial Dysfunction in Association with Activation of the Renin‐Angiotensin Aldosterone System
Authors: Faulkner Jessica L. , Harwood Daisy , Bender Lily , Morwitzer Jane , Brands Michael , Kennard Simone , Antonova Galina , Belin de Chantemele Eric J. 
Published: June 2021

Clinical data suggest that salt‐sensitive hypertension is more prominent in woman than men. In contrast, current rodent models of salt‐sensitivity demonstrate more pronounced salt‐sensitive phenotypes in males than females. Therefore, the sex‐specific mechanisms via which females develop salt‐sensitive hypertension are poorly understood. Our lab has found that high salt diet (HS) induces sex‐specific increases in mean arterial pressure (BP) in female Balb/C mice. We have also previously shown that mineralocorticoid receptor (MR) activation is implicated in BP and endothelial regulation in female, but not male, mouse models of hypertension. However, whether renin‐angiotensin aldosterone system (RAAS) activation, and subsequent increase in MR activity, is implicated in female Balb/C salt‐sensitive hypertension is unknown. Therefore, we hypothesized that HS‐induced hypertension and endothelial dysfunction in female Balb/C mice is associated with increased RAAS activation and ablated by MR inhibition. To assess BP in male and female Balb/C mice, 10 week old mice were implanted with radiotelemeters (carotid artery) for continuous recording of BP during baseline (normal 0.2% salt (NS) diet, 7 days) and HS feeding (0.4% NaCl, 7 days). BP increased in female mice in response to HS (104.6±3.5 NS vs 114.0±2.8 HS mmHg, P<0.05, n=5), however, no such increase was observed in male mice (102.6±4.0 NS vs 102.1±3.4 HS mmHg, n=5). Endothelial function was assessed as vascular relaxation to acetylcholine (10−9M–10−5M, nonlinear fit curve). HS female mice demonstrated impaired endothelial function compared to NS females (P<0.05, n=7–8) while no such dysfunction developed in HS male mice (n=7–8). RT‐PCR analysis of renal tissues showed that mRNA expression of renin (1.4±0.1‐fold change, P<0.05, n=5), angiotensinogen (4.4±0.2‐fold change, P<0.05, n=5), MR (1.6±0.2‐fold change, P<0.05, n=5) and epithelial sodium channel‐α (1.3±0.1‐fold change, P<0.05, n=5) were increased by HS in female mice compared to NS females, indicating an activation of RAAS by HS in Balb/C females. Of the RAAS mRNA expressions assessed, only renal MR mRNA expression was increased in male mice on HS compared to NS males (1.30±0.1‐fold change, P<0.05, n=5). Importantly, plasma aldosterone levels were decreased in male HS mice compared to NS males (490±135 NS vs 160±35 HS pg/ml, P<0.05, n=8–16), however, HS did not decrease aldosterone levels in female mice compared to NS females (562±125 NS vs 334±64 HS pg/ml, n=9–15), demonstrating a sex‐specific preservation of aldosterone levels in the presence of HS in female Balb/C mice. Furthermore, BP increases and endothelial dysfunction in HS female mice were ablated in response to the MR antagonist eplerenone (200 ng/kg/day, drinking water) (96.1±7.1 mmHg, P<0.05, n=4), whereas no effects were observed in male HS eplerenone mice (106.1±5.8 mmHg, n=4). These data indicate that female Balb/C mice develop sex‐specific hypertension and endothelial dysfunction in association with RAAS activation which is dependent on MR activation. Therefore, the female Balb/C mouse may be an important model for studies of the mechanisms of salt‐sensitive hypertension in women.Support or Funding InformationThis work was supported by the following: NIH 1R01HL130301‐01, AHA 16IRG27770047, NIH 5F32HL136191‐02This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.