Keratinocyte-specific angiotensin II receptor-associated protein deficiency exacerbates angiotensin II-dependent hypertension via activation of the skin renin-angiotensin system

Shinya Taguchi, Kengo Azushima (), Kento Kitada, Norihiko Morisawa, Satoshi Kidoguchi, Ryutaro Morita, Kazuya Nakagawa, Atsushi Ishibe, Itaru Endo, Keisuke Kazama, Yasushi Rino, Aya Saito, Sho Kinguchi, Ryu Kobayashi, Taiji Matsusaka, Akio Yamashita, Hiromichi Wakui (), Akira Nishiyama and Kouichi Tamura
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Shinya Taguchi: Yokohama City University Graduate School of Medicine
Kengo Azushima: Yokohama City University Graduate School of Medicine
Kento Kitada: Kagawa University
Norihiko Morisawa: Duke-NUS Medical School
Satoshi Kidoguchi: The Jikei University School of Medicine
Ryutaro Morita: Yokohama City University Graduate School of Medicine
Kazuya Nakagawa: Yokohama City University Graduate School of Medicine
Atsushi Ishibe: Yokohama City University Graduate School of Medicine
Itaru Endo: Yokohama City University Graduate School of Medicine
Keisuke Kazama: Yokohama City University
Yasushi Rino: Yokohama City University
Aya Saito: Yokohama City University
Sho Kinguchi: Yokohama City University Graduate School of Medicine
Ryu Kobayashi: Yokohama City University Graduate School of Medicine
Taiji Matsusaka: Tokai University School of Medicine
Akio Yamashita: University of the Ryukyus
Hiromichi Wakui: Yokohama City University Graduate School of Medicine
Akira Nishiyama: Kagawa University
Kouichi Tamura: Yokohama City University Graduate School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60041-8

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DOI: 10.1038/s41467-025-60041-8

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