ArticleJCI insight2023
P2Y2 receptor decreases blood pressure by inhibiting ENaC.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 8 citations in OpenAlex.
- GPER1 activation regulates renal purinergic P2YAmerican journal of physiology. Regulatory, integrative and comparative physiology · 2026Article
- Current understanding of ENaC regulation by P2Y2/PLC/PI(4,5)P2 pathway.Purinergic signalling · 2026Review
- Renal G protein-coupled estrogen receptor 1 regulates the epithelial sodium channel promoting natriuresis to a greater extent in females.American journal of physiology. Renal physiology · 2025Article
- Gi-DREADD activation decreases Epithelial NaPhysiological reports · 2025Article
- G protein-coupled receptor-mediated renal fibrosis: a key focus on kidney disease drug development.Frontiers in pharmacology · 2025Review
- Purinergic Receptor Antagonists: A Complementary Treatment for Hypertension.Pharmaceuticals (Basel, Switzerland) · 2024Review
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Authors and funding
6 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to participate in P2ry2 effects on blood pressure. To isolate the role of the kidneys in P2ry2 effects on blood pressure and to reveal the molecular and cellular mechanisms of this action, we test here the necessity of the P2ry2 and the sufficiency of Gq-dependent signaling in renal principal cells to the regulation of the epithelial Na+ channel (ENaC), sodium excretion, and blood pressure. Activating P2ry2 in littermate controls but not principal cell-specific P2ry2-knockout mice decreased the activity of ENaC in renal tubules. Moreover, deletion of P2ry2 in principal cells abolished increases in sodium excretion in response to stimulation of P2ry2 and compromised the normal ability to excrete a sodium load. Consequently, principal cell-specific knockout of P2ry2 prevented decreases in blood pressure in response to P2ry2 stimulation in the deoxycorticosterone acetate-salt (DOCA-salt) model of hypertension. In wild-type littermate controls, such stimulation decreased blood pressure in this model of hypertension by promoting a natriuresis. Pharmacogenetic activation of Gq exclusively in principal cells using targeted expression of Gq-designer receptors exclusively activated by designer drugs and clozapine N-oxide decreased the activity of ENaC in renal tubules, promoting a natriuresis that lowered elevated blood pressure in the DOCA-salt model of hypertension. These findings demonstrate that the kidneys play a major role in decreasing blood pressure in response to P2ry2 activation and that inhibition of ENaC activity in response to P2ry2-mediated Gq signaling lowered blood pressure by increasing renal sodium excretion.
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