A 7-day high-salt diet induced an 8.4 ± 4.6 mmHg rise in blood pressure in female BALB/cJ mice, driven by leptin-mediated aldosterone synthesis and increased ECMR expression.
The leptin-aldosterone-ECMR axis is a key mechanistic pathway driving salt-sensitive hypertension and endothelial dysfunction in young females, offering a potential therapeutic target.
Excess salt consumption overrides the cardioprotective effects of female sex, and a significant proportion of women of reproductive age develop salt-sensitivity of blood pressure (SSBP). Yet, the etiopathophysiology underlying SSBP in young women remains poorly defined. Using radiotelemetry, we identified BALB/cJ females as the first endogenous rodent model of SSBP, exhibiting a 8.4 ± 4.6 mmHg rise in blood pressure (BP) after 7 days on a high-salt diet (4% NaCl). In contrast, HSD-fed C57BL/6J remained resistant to salt-mediated increases in BP. Neither acute natriuresis in response to the salt-loading test nor 24-h urinary sodium excretion indicated salt retention in BALB/cJ mice. However, HSD markedly attenuated acetylcholine (ACh)-mediated relaxation in mesenteric arteries, as well as ACh-mediated increases in renal perfusion, in BALB/cJ mice only, indicating impaired endothelium-dependent vasodilation. Salt-resistant (SR) C57BL/6J mice showed intact vascular responses regardless of salt intake. Additionally, HSD-fed BALB/cJ mice exhibited a ~3-fold increase in endothelial mineralocorticoid receptor (ECMR) expression. In SR C57BL/6 mice, HSD lowered plasma aldosterone levels. In opposition, salt-sensitive BALB/cJ mice failed to suppress aldosterone production. Instead, they showed increased adrenal aldosterone synthase (CYP11B2) and leptin receptor (LepRb) transcript and protein levels, paralleling elevated plasma leptin levels, despite no alterations in body weight. Given that leptin is a direct positive regulator of aldosterone production, we hypothesized that leptin-mediated aldosterone-ECMR overactivation is central to female SSBP. Systemic LepR blockade with the LepR antagonist Allo-aca restored BP and ACh-dependent relaxation in HSD-fed BALB/cJ mice, concurrently reducing ECMR expression. Conversely, seven-day leptin infusion in HSD-fed female SR-C57BL/6J mice induced SSBP and reproduced HSD-like vasodilatory impairment, elevated aldosterone, and increased ECMR expression. Moreover, leptin infusion paired with aldosterone synthase inhibition using Baxdrostat resulted in a downward trend in BP and rescued endothelial function. To define the causal role of heightened ECMR, we generated an endothelial-specific MR-overexpressing (ECMR-OE) mouse on the C57BL/6J background. Female ECMR-OE mice exhibited increased BP and impaired endothelial vasodilation, phenocopying SS-BALB/cJ mice. To establish human relevance, endothelial cells derived from healthy premenopausal donors were treated with increasing concentrations of aldosterone, resulting in a dose-dependent increase in ECMR expression. In conclusion, these findings indicate that HSD-induced leptin elevation activates aldosterone synthesis and increases ECMR expression, culminating in endothelial dysfunction and SSBP. Thus, targeting the leptin-aldosterone-ECMR axis may offer novel therapeutic avenues to remediate SSBP in young women. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Menik et al. (Fri,) conducted a other in Salt-sensitive hypertension. High-salt diet vs. Salt-resistant C57BL/6J mice was evaluated on Blood pressure rise. A 7-day high-salt diet induced an 8.4 ± 4.6 mmHg rise in blood pressure in female BALB/cJ mice, driven by leptin-mediated aldosterone synthesis and increased ECMR expression.