Role of G-protein-coupled receptor kinase 4 on the dysfunction of renal Mas receptor in hypertension.
The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis plays an important role in the regulation of blood pressure. G protein-coupled receptor kinase 4 (GRK4) has attracted more attentions by modulating G protein-coupled receptors and blood pressure. However, it remains unknown whet...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0329547 |
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| Summary: | The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis plays an important role in the regulation of blood pressure. G protein-coupled receptor kinase 4 (GRK4) has attracted more attentions by modulating G protein-coupled receptors and blood pressure. However, it remains unknown whether renal Mas receptor is regulated by GRK4 and its role in the pathogenesis of hypertension. Compared with Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) exhibited impaired Mas receptor-mediated diuresis and natriuresis, which was accompanied with increased phosphorylation levels of Mas receptors. Similarly, the phosphorylation of renal Mas receptor was increased and its-induced renal effects were decreased in human (h) GRK4γ 142V transgenic mice relative to wild-type littermates. There was a colocalization and a direct interaction of renal Mas receptor and GRK4, which were increased in SHRs and confirmed by rigid protein-protein docking. In vitro studies found that treatment with the Mas receptor agonist AVE0991 inhibited Na+-K+-ATPase activity in WKY renal proximal tubule (RPT) cells, which was failed in SHR cells. GRK4 silencing decreased the phosphorylation of Mas receptor and improved the impaired Mas receptor-mediated inhibition of Na+-K+-ATPase activity in SHR RPT cells. Further study showed that ultrasound-targeted microbubble destruction-targeted renal GRK4 depletion decreased Mas receptor phosphorylation and improved its-induced diuresis and natriuresis in SHRs. These suggest that GRK4 contributes to increased renal Mas receptor phosphorylation and dysfunction in hypertension, indicating that targeting GRK4 may be a viable therapeutic approach for hypertension. |
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| ISSN: | 1932-6203 |