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Trimethylation of Histone 3 Lysine 4 on Hypothalamic (Pro)renin Receptor Mediates the Development of DOCA‐salt Hypertension.

We reported that brain (pro)renin receptor (PRR) expression is elevated in deoxycorticosterone acetate (DOCA)‐salt hypertension; however, the underlining mechanism remains unknown. To test our hypothesis that epigenetic mechanism is involved in the regulation of PRR expression in DOCA‐salt hypertension, C57Bl/6J mice were implanted with SHAM or DOCA 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), which was not altered by ICV infusion of losartan (2.33±0.27). Importantly, we found increased H3K4 methyltransferases (HMT) activity (OD/hour/mg protein), an enzyme complex responsible for H3K4 methylation, after DOCA‐salt treatment (44.54±2.09, P<0.05) compared with SHAM (28.23±2.05). To examine the contribution of H3K4me3 on PRR expression and the increased BP during DOCA‐salt hypertension, mice were treated with DOCA‐salt and ICV infused with either artificial CSF or 5'‐methylthioadenosine (MTA), a specific methyltransferase inhibitor, for 3 weeks. ICV infusion of MTA normalized the increase in H3K4me3 (0.9±0.11), HMT activity (32.3±2.38) compared with ICV aCSF in DOCA‐salt treated mice. ICV infusion of MTA attenuated PRR mRNA levels (1.4±0.1 vs. 2.4±0.2) and BP (123.1±6.3 vs. 138.5±7.4 mmHg) compared with control following DOCA‐salt treatment. In summary, H3K4me3 on PRR promoter is a key epigenetic mechanism for the up‐regulation of brain PRR and the increase in BP during salt‐sensitive hypertension.