論文 - 詳細
| RRC ID | 81545 |
|---|---|
| 著者 | Okamoto Y, Kitakaze K, Takenouchi Y, Matsui R, Koga D, Miyashima R, Ishimaru H, Tsuboi K. |
| タイトル | GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression. |
| ジャーナル | Biochim Biophys Acta Mol Cell Res |
| Abstract |
Fibrosis is characterized by excessive deposition of extracellular matrix proteins, particularly collagen, caused by myofibroblasts in response to chronic inflammation. Although G protein-coupled receptors (GPCRs) are among the targets of current antifibrotic drugs, no drug has yet been approved to stop fibrosis progression. Herein, we aimed to identify GPCRs with profibrotic effects. In gene expression analysis of mouse lungs with induced fibrosis, eight GPCRs were identified, showing a >2-fold increase in mRNA expression after fibrosis induction. Among them, we focused on Gpr176 owing to its significant correlation with a myofibroblast marker α-smooth muscle actin (αSMA), the profibrotic factor transforming growth factor β1 (TGFβ1), and collagen in a human lung gene expression database. Similar to the lung fibrosis model, increased Gpr176 expression was also observed in other organs affected by fibrosis, including the kidney, liver, and heart, suggesting its role in fibrosis across various organs. Furthermore, fibroblasts abundantly expressed Gpr176 compared to alveolar epithelial cells, endothelial cells, and macrophages in the fibrotic lung. GPR176 expression was unaffected by TGFβ1 stimulation in rat renal fibroblast NRK-49 cells, whereas knockdown of Gpr176 by siRNA reduced TGFβ1-induced expression of αSMA, fibronectin, and collagen as well as Smad2 phosphorylation. This suggested that Gpr176 regulates fibroblast activation. Consequently, Gpr176 acts in a profibrotic manner, and inhibiting its activity could potentially prevent myofibroblast differentiation and improve fibrosis. Developing a GPR176 inverse agonist or allosteric modulator is a promising therapeutic approach for fibrosis. |
| 巻・号 | 1871(7) |
| ページ | 119798 |
| 公開日 | 2024-10-1 |
| DOI | 10.1016/j.bbamcr.2024.119798 |
| PII | S0167-4889(24)00141-1 |
| PMID | 39047914 |
| MeSH | Actins / genetics Actins / metabolism Animals Disease Progression Fibroblasts* / metabolism Fibroblasts* / pathology Fibrosis* Humans Lung / metabolism Lung / pathology Male Mice Mice, Inbred C57BL Myofibroblasts* / metabolism Myofibroblasts* / pathology Pulmonary Fibrosis / genetics Pulmonary Fibrosis / metabolism Pulmonary Fibrosis / pathology Rats Receptors, G-Protein-Coupled* / genetics Receptors, G-Protein-Coupled* / metabolism Transforming Growth Factor beta1 / genetics Transforming Growth Factor beta1 / metabolism |
| IF | 4.105 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | NRK49F(RCB0112) 293(RCB1637) WI-38(RCB0702) |