Abstract 6: Angiotensin II via Its Type 1 Receptor Up-regulates (Pro)renin Receptor Expression in Doca-salt Hypertension

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Abstract

We previously reported that brain (pro)renin receptor (PRR) expression levels are elevated in deoxycorticosterone acetate (DOCA)-salt induced hypertension; however, the underlining mechanism remains unknown. To address whether angiotensin (Ang II) type 1 receptor (AT1R) signals are involved in the regulation of PRR expression in DOCA-salt hypertension, C57Bl/6J mice were implanted with telemetry transmitters. After two weeks recovery, mice were treated with DOCA (50mg) or SHAM pellet, and supplied with 0.9% saline as drinking solution; at the same time, mice were ICV infused with artificial CSF or AT1R blocker losartan (3mg/kg/day) for 3 weeks. The mean arterial BP was significantly higher in DOCA-salt (132.3±6.3mmHg) compared to SHAM (100.2±2.3mmHg) mice. ICV infusion of losartan prevented the increase in BP (107.4±2.7mmHg) following DOCA-salt treatment. The PRR mRNA levels (fold change) were significantly increased in the paraventricular nucleus (PVN) of DOCA-salt (2.9±0.3) compared with SHAM mice (1.0±0.1, P<0.05). Interestingly, ICV infusion of losartan significantly attenuated PRR mRNA levels in the PVN (1.3±0.1) following DOCA-salt treatment (P<0.05). These data suggest a role of Ang II/AT1R in regulating PRR expression during DOCA-salt hypertension. A transcription factor prediction search showed cAMP response element-binding protein (CREB), activator protein-1 binding protein (AP-1), and NF-kB binding sites on the PRR promoter region. To test whether these Ang II/AT1R downstream transcription factors are involved in PRR regulation, Neuro-2A cells were treated with Ang II (100nM, 2 h) with or without CREB (CBP-CREB interaction inhibitor, 10μM), AP-1 (SR-11302, 10μM), or NF-κB (parthenolide, 10μM) inhibitors. PRR mRNA levels (fold change) were slightly but significantly increased (1.3±0.1 vs. vehicle, P<0.05) following Ang II treatment. CREB (0.8±0.2) or AP-1 (0.7±0.1) inhibitor abolished the increase in PRR mRNA induced by Ang II (P<0.01). The NF-kB inhibitor had no effect on Ang II-induced PRR mRNA elevation. In conclusion, Ang II via AT1R up-regulates PRR mRNA expression in the PVN of DOCA-hypertensive mice possibly through activation of CREB and AP-1 signaling pathways.

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