title: Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension.
abstract: The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR), promoted Ang II-induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II-induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein-dependent vascular hypertrophy but reduced β-arrestin-dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II-induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin-dependent proliferation to G protein-dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II.
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan. SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan. Department of Biomedical Science and Therapeutic, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah 88400 Malaysia. Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sunggip
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tozaki-Saitoh
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan. Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shimauchi
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan. SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Numaga-Tomita
authors.affiliation: Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirano
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.affiliation: Institute of Interdisciplinary Research, School of Medicine, Université Libre de Bruxelles, Gosselies 6041, Belgium.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.affiliation: Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
authors.affiliation: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Institute of Interdisciplinary Research, School of Medicine, Université Libre de Bruxelles, Gosselies 6041, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan. SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Hayama, Kanagawa 240-0193, Japan. Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. nishida@nips.ac.jp.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055503:Protein Multimerization / Q000187:drug effects* / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D000804:Angiotensin II