Impact of Leptin and Aldosterone on Blood Pressure Regulation in Female Mice

Salt abrogates the cardioprotective effects of female sex. However, the mechanisms whereby women develop salt sensitivity of blood pressure (SSBP) remain unclear. Using radiotelemetry, we report that female Balb/C mice exhibit an 8.4±4.6 mmHg blood pressure (BP) increase (P<0.05) in response to a 7-day high salt diet (HSD; 4% NaCl) when C57Bl/6 female mice show no rise in BP, making the female Balb/C mouse the first rodent model to develop SSBP spontaneously. Acute natriuresis assessment via salt-loading test or 24-hour urinary sodium excretion showed no increase in salt retention in Balb/C mice. Remarkably, while HSD markedly reduced aldosterone in salt-resistant (SR) C57Bl/6 mice, aldosterone production remained unsuppressed in Balb/C mice, which also exhibited elevated adrenal aldosterone synthase and leptin receptor (LepR) expression, concomitant with high plasma leptin levels. Moreover, HSD impaired mesenteric artery relaxation to acetylcholine (ACh), indicating impaired endothelium-dependent function in Balb/C mice. Excitingly, in-vivo data on renal perfusion obtained via functional ultrasound revealed that HSD-fed Balb/C mice exhibited blunted ACh-induced relaxation compared to their normal salt diet (NSD; 0.2% NaCl)-fed counterparts. In contrast, NSD- and HSD-fed C57Bl/6 mice maintained a robust vascular response. Additionally, Balb/C showed a 3-fold increase in endothelial cell mineralocorticoid receptor (ECMR) expression. Thus, we hypothesized that female Balb/C mice develop SSBP via leptin-mediated, aldosterone-induced ECMR activation. Treatment with the LepR antagonist, Allo-aca, restored BP and ACh-mediated relaxation in HSD-fed Balb/C mice. Leptin infusion in female SR-C57BL/6 mice fed an HSD induced SSBP and replicated the HSD-mediated vasodilatory impairment. Furthermore, aldosterone synthase inhibition with Baxdrostat reduced BP and rescued endothelial function in HSD-fed Balb/C mice. To test the contribution of enhanced ECMR to SSBP, we generated a mouse on the C57Bl/6 background with a selective MR overexpression in endothelial cells (ECMR-OE). Female ECMR-OE mice exhibited elevated BP and endothelial dysfunction, mirroring SS-Balb/C mice. Our multi-approach study suggests that HSD-induced leptin overproduction drives aldosterone synthesis and ECMR upregulation, culminating in endothelial dysfunction and SSBP in female mice. Targeting the leptin-aldosterone-ECMR axis may offer novel therapeutic avenues to mitigate SSBP in young women.