Keratinocyte-specific angiotensin II receptor-associated protein deficiency exacerbates angiotensin II-dependent hypertension via activation of the skin reninangiotensin system
2025.05.30
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) type1 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 RASmay become a potential strategy for therapeutic interventions in hypertension.
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Kengo Azushima
Lecturer
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Hiromichi Wakui
Associate Professor
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Kouichi Tamura
Professor
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Itaru Endo
Professor
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan;
Lecturer
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Hiromichi Wakui
Associate Professor
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Kouichi Tamura
Professor
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Itaru Endo
Professor
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan;