Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension

Akiyuki Nishimura, Caroline Sunggip, Hidetoshi Tozaki-Saitoh, Tsukasa Shimauchi, Takuro Numaga-Tomita, Katsuya Hirano, Tomomi Ide, Jean Marie Boeynaems, Hitoshi Kurose, Makoto Tsuda, Bernard Robaye, Kazuhide Inoue, Motohiro Nishida

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 b-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 vascularsmoothmuscle 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.

Original languageEnglish
Article numberaac9187
JournalScience Signaling
Volume9
Issue number411
DOIs
Publication statusPublished - Jan 19 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Purinergic P2Y<sub>6</sub> receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension'. Together they form a unique fingerprint.

  • Cite this