Abstract 045: Epigenetic Modification of Brain (pro)renin Receptor Contributes to the Development of Doca-salt Hypertension via Epithelial Sodium Channel

Abstract

We reported that elevated brain (pro)renin receptor (PRR) expression levels contributes to the development of salt-sensitive hypertension (SSH); however, the underlining mechanism on how PRR is regulated remains unknown. High-salt intake is a major life style epigenetic factors for the SSH. To test our hypothesis that epigenetic mechanism is involved in the regulation of PRR expression in SSH, we used deoxycorticosterone acetate (DOCA)-salt induced hypertension as a model of SSH. C57Bl/6J mice (n=5/group) were implanted with SHAM or DOCA (50mg) pellet and supplied with saline for 3 weeks. Histone modifications on PRR promoter were assessed in the hypothalamus using Chromatin Immunoprecipitation assays at the end of protocol. We found an increase (fold change) in histone 3 lysine 4 trimethylation (H3K4me3) on the PRR promoter in DOCA-salt (2.45±0.36) compared with SHAM treated mice (1.00±0.16, P<0.05). H3K4 methyltransferases (HMT) activity (OD/hour/mg protein), an enzyme complex responsible for H3K4 methylation is increased after DOCA-salt treatment (45±2, P<0.05) compared with SHAM (28±2). To examine the mechanisms of elevated HMT activity during DOCA-salt hypertension, we treated culture neurons (n=3 independent experiments/group) with control (155mM sodium), high salt (170 mM sodium), aldosterone (100 nM), or high salt+aldosterone with or without epithelial sodium channel (ENaC) blocker (amiloride, 100 nM) for 2 hours and test the HMT activity and PRR expression levels. High salt or aldosterone alone has minimal effects on HMT activity and PRR levels. High salt+aldosterone significantly increased HMT activity (41±3 vs. 24±2, P<0.05) and PRR mRNA (1.6±0.1 vs. 1.0±0.1 fold change, P<0.05) levels compare to control. Amiloride attenuated HMT activity (25±4.1, P<0.05) and PRR mRNA levels (0.98±0.1, P<0.05) compared to high salt+aldosterone treatment. In summary, elevated PRR expression is associated with increased HMT activity and H3K4me3 modification on PRR promoter. ENaC blockade attenuates the elevation of HMT activity and PRR levels induced by high salt+aldosterone in culture neurons. We conclude that ENaC may be responsible for epigenetic up-regulation of brain PRR and thus the increase in BP during salt-sensitive hypertension.