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Enhancement of angiotensin II type 1 receptor-associated protein in the paraventricular nucleus suppresses angiotensin II-dependent hypertension

Hypertension Research volume 47, pages 67–77 (2024)Cite this article

Abstract

The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.

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Data availability

All relevant data were included in this study. These datasets are available from the corresponding authors upon request.

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Acknowledgements

This work was supported with grants from the Yokohama Foundation for Advancement of Medical Science, Uehara Memorial Foundation, Japan Society for the Promotion of Science, Japan Kidney Association-Nippon Boehringer Ingelheim Joint Research Program, Japanese Association of Dialysis Physicians, Salt Science Research Foundation, Strategic Research Project of Yokohama City University, the Japan Agency for Medical Research and Development (AMED), Translational Research Program, Strategic Promotion for Practical Application of Innovative Medical Technology (TR-SPRINT) from AMED, Moriya Scholarship Foundation, Bayer Scholarship for Cardiovascular Research, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Yokohama City University research grant “KAMOME Project”.

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  1. These authors contributed equally: Mari Sotozawa, Sho Kinguchi

Authors and Affiliations

  1. Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Mari Sotozawa, Sho Kinguchi, Hiromichi Wakui, Kengo Azushima & Kouichi Tamura

  2. Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama, Japan

    Kengo Funakoshi

  3. Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Waki Nakajima, Tomoyuki Miyazaki & Takuya Takahashi

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Contributions

MS, SK, and HW designed and conducted the study. MS, HW, and KA wrote the manuscript. MS, SK, HW, KA, and WN performed the experiments. MS and SK analyzed the data. KF, TM, TT, and KT supervised the study. All authors have approved the final manuscript.

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Correspondence to Hiromichi Wakui or Kengo Azushima.

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Sotozawa, M., Kinguchi, S., Wakui, H. et al. Enhancement of angiotensin II type 1 receptor-associated protein in the paraventricular nucleus suppresses angiotensin II-dependent hypertension. Hypertens Res 47, 67–77 (2024). https://doi.org/10.1038/s41440-023-01480-y

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