ROLE OF BRAIN ALDOSTERONE AND MINERALOCORTICOID RECEPTORS IN ALDOSTERONE-SALT HYPERTENSION IN RATS

Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT(1)Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT(1)R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1 mu g/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-AT(1a)R-siRNA. Infusion of aldo had no effect on 11 beta HSD2, MR and AT(1)R mRNA in different nuclei but increased CYP11B2 mRNA in the SFO, and serum and glucocorticoid-kinase 1 (Sgk1) and epithelial sodium channel (ENaC) gamma subunit mRNA in the SFO and supraoptic nucleus (SON). MR-siRNA decreased both MR and AT(1)R mRNA in the PVN by similar to 60%, but AT(1a)R-siRNA only decreased AT(1)R mRNA. SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT(1)R in the PVN similarly attenuated aldosterone-induced saline intake by similar to 50% and hypertension by similar to 70%. These results suggest that an increase in circulating aldosterone may via MR and AT(1)R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT(1)R signaling in the PVN. This central aldosterone-MR-AT(1)R neuro-modulatory pathway appears to play a major role in the progressive hypertension. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.