P2Y2 receptor decreases blood pressure by inhibiting ENaC
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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-07-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.167704 |
| _version_ | 1797634295073865728 |
|---|---|
| author | Antonio G. Soares Jorge Contreras Elena Mironova Crystal R. Archer James D. Stockand Tarek Mohamed Abd El-Aziz |
| author_facet | Antonio G. Soares Jorge Contreras Elena Mironova Crystal R. Archer James D. Stockand Tarek Mohamed Abd El-Aziz |
| author_sort | Antonio G. Soares |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:05:36Z |
| format | Article |
| id | doaj.art-5d5dc24c02d7416984fc18d03aff5ff9 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:36Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-5d5dc24c02d7416984fc18d03aff5ff92023-11-07T16:25:53ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-07-01814P2Y2 receptor decreases blood pressure by inhibiting ENaCAntonio G. SoaresJorge ContrerasElena MironovaCrystal R. ArcherJames D. StockandTarek Mohamed Abd El-AzizStimulating 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.https://doi.org/10.1172/jci.insight.167704Cell biologyNephrology |
| spellingShingle | Antonio G. Soares Jorge Contreras Elena Mironova Crystal R. Archer James D. Stockand Tarek Mohamed Abd El-Aziz P2Y2 receptor decreases blood pressure by inhibiting ENaC JCI Insight Cell biology Nephrology |
| title | P2Y2 receptor decreases blood pressure by inhibiting ENaC |
| title_full | P2Y2 receptor decreases blood pressure by inhibiting ENaC |
| title_fullStr | P2Y2 receptor decreases blood pressure by inhibiting ENaC |
| title_full_unstemmed | P2Y2 receptor decreases blood pressure by inhibiting ENaC |
| title_short | P2Y2 receptor decreases blood pressure by inhibiting ENaC |
| title_sort | p2y2 receptor decreases blood pressure by inhibiting enac |
| topic | Cell biology Nephrology |
| url | https://doi.org/10.1172/jci.insight.167704 |
| work_keys_str_mv | AT antoniogsoares p2y2receptordecreasesbloodpressurebyinhibitingenac AT jorgecontreras p2y2receptordecreasesbloodpressurebyinhibitingenac AT elenamironova p2y2receptordecreasesbloodpressurebyinhibitingenac AT crystalrarcher p2y2receptordecreasesbloodpressurebyinhibitingenac AT jamesdstockand p2y2receptordecreasesbloodpressurebyinhibitingenac AT tarekmohamedabdelaziz p2y2receptordecreasesbloodpressurebyinhibitingenac |