Keratinocyte-specific angiotensin II receptor-associated protein deficiency exacerbates angiotensin II-dependent hypertension via activation of the skin renin-angiotensin system
The skin has recently been highlighted as a new player regulating blood pressure (BP). Here we show the role of skin renin-angiotensin system (RAS) in hypertension. In human subjects, skin expression of angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP), which inhibits pathological AT1R signaling, is inversely correlated with systolic BP. Keratinocyte-specific ATRAP knockout male mice (KO) exhibit exacerbated Ang II-induced hypertension and skin-specific increases in angiotensinogen and Ang II levels. In keratinocyte-specific ATRAP and AT1R knockout male mice, Ang II-induced skin angiotensinogen excess and exaggerated hypertension seen in KO are eliminated. Although body fluid volume is comparable between the genotypes, the urine volume per water intake in Ang II-infused KO is increased, suggesting decreased extra-renal water loss, which is supported by decreased skin blood flow and transepidermal water loss in KO. Body temperature elevation-induced skin vasodilation eliminates these differences, including exaggerated hypertension, indicating the contribution of skin RAS-mediated vasoconstriction to BP elevation. Skin RAS may become a potential strategy for therapeutic interventions in hypertension.
Authors
- Shinya Taguchi (ORCID: https://orcid.org/0000-0002-4540-125X)
- Satoshi Kidoguchi (ORCID: https://orcid.org/0000-0001-8114-8952)
- Ryutaro Morita
- Norihiko Morisawa (ORCID: https://orcid.org/0000-0002-1761-3888)
- Hiromichi Wakui (ORCID: https://orcid.org/0000-0001-8023-922X)
- Taiji Matsusaka (ORCID: https://orcid.org/0000-0001-9466-4585)
- Kengo Azushima (ORCID: https://orcid.org/0000-0002-5136-0730)
- Kento Kitada (ORCID: https://orcid.org/0000-0002-6738-1253)
- Akira Nishiyama (ORCID: https://orcid.org/0000-0001-5971-820X)
- Atsushi Ishibe (ORCID: https://orcid.org/0000-0002-3251-3658)
- Kouichi Tamura (ORCID: https://orcid.org/0000-0002-0660-5372)
- Akio Yamashita (ORCID: https://orcid.org/0000-0001-7095-4473)
- Sho Kinguchi (ORCID: https://orcid.org/0009-0007-0952-8548)
- Keisuke Kazama (ORCID: https://orcid.org/0000-0002-8155-8561)
- Kazuya Nakagawa (ORCID: https://orcid.org/0000-0002-7504-7255)
- Yasushi Rino
- Ryu Kobayashi
- Itaru Endo (ORCID: https://orcid.org/0000-0002-3202-2752)
- Aya Saito
Institutions
- Jikei University School of Medicine (JP)
- Tokai University (JP)
- Kagawa University (JP)
- Yokohama City University Medical Center (JP)
- University of the Ryukyus (JP)
- Duke-NUS Medical School (SG)
- Yokohama City University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1038/s41467-025-60041-8
- Citations
- 4
- Primary Topic
- Renin-Angiotensin System Studies
- Type
- article
- Field-Weighted Citation Impact
- 5.55
Funders
- Boehringer Ingelheim Japan
- Japanese Association of Dialysis Physicians
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Hokkaido University
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Co-creation place formation support program