Role of brain aldosterone and mineralocorticoid receptors in aldosterone-salt hypertension in rats

•SFO lesion, central aldo synthase or MR blocker and knockdown of MR or AT1R in the PVN were assessed.•All interventions similarly attenuate aldosterone-induced saline intake and hypertension.•AAV-MR-siRNA decreases both MR and AT1R mRNA in the PVN, but AT1aR-siRNA only decreases AT1R mRNA.•Plasma aldosterone may via MR and AT1R in SFO increase aldosterone-MR-AT1R signaling in the PVN.•Central mechanisms converging in the PVN play a major role in the aldosterone-salt hypertension.

Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1 μg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. Other sets of rats received chronic intra-cerebroventricular (icv) infusion of aldo synthase (AS) inhibitor FAD286, MR blocker eplerenone or vehicle, electrolytic or sham lesions of the SFO, or intra-PVN infusion of AAV-MR-siRNA or AAV-AT1aR-siRNA. Infusion of aldo had no effect on 11βHSD2, MR and AT1R mRNA in different nuclei but increased CYP11B2 mRNA in the SFO, and serum and glucocorticoid-kinase 1 (Sgk1) and epithelial sodium channel (ENaC) γ subunit mRNA in the SFO and supraoptic nucleus (SON). MR-siRNA decreased both MR and AT1R mRNA in the PVN by ∼60%, but AT1aR-siRNA only decreased AT1R mRNA. SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼50% and hypertension by ∼70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.

Graphical abstractSFO lesion, central infusion of an aldosterone synthase inhibitor or MR blocker and knockdown of MR or AT1R expression in the PVN similarly prevent ∼70% of aldosterone-salt hypertension. Central mechanisms appear to play a major role in the hypertension induced by aldosterone-salt.*p < 0.05, vs. other groups.Download high-res image (98KB)Download full-size image