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AM251 Suppresses Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells
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| Title: | AM251 Suppresses Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells |
| Authors: | Yoshinaga, Tomoyo Browse this author | | Uwabe, Kenichiro Browse this author | | Naito, Shoichi Browse this author | | Higashino, Kenichi Browse this author | | Nakano, Toru Browse this author | | Numata, Yoshito Browse this author | | Kihara, Akio Browse this author →KAKEN DB |
| Issue Date: | 9-Dec-2016 |
| Publisher: | PLOS |
| Journal Title: | PLoS ONE |
| Volume: | 11 |
| Issue: | 12 |
| Start Page: | e0167848 |
| Publisher DOI: | 10.1371/journal.pone.0167848 |
| Abstract: | Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the causative mechanisms of kidney fibrosis. In our study, we screened lipophilic compounds using a lipid library including approximately 200 lipids to identify those that suppressed EMT induced by a transforming growth factor (TGF)-beta 1 stimulus. Initial screening was performed with the immortalized HK-2 renal tubule epithelial cell line. The most promising compounds were further tested in RPTEC primary renal tubule epithelial cells. We found that the synthetic lipid AM251 suppressed two hallmark events associated with EMT, the upregulation of collagen 1A1 (COL1A1) and downregulation of E-cadherin. Though AM251 is known to act as an antagonist for the cannabinoid receptor type 1 (CB1) and an agonist for the G protein-coupled receptor 55 (GRP55), the suppression of EMT by AM251 was not mediated through either receptor. Microarray analyses revealed that AM251 inhibited induction of several EMT transcription factors such as SNAIL1, which is the key inducer of EMT, and the AP-1 transcription factors FOSB and JUNB. Activation of SMAD2/3 and p38 mitogen-activated protein kinase (MAPK) was inhibited by AM251, with greater inhibition of the latter, indicating that AM251 acted upstream of SMAD/p38 MAPK in the TGF-beta signaling pathway. Our findings regarding the effects of AM251 on the TGF-beta signaling pathway may inform development of a novel therapeutic agent suppressing EMT, thus preventing kidney fibrosis. |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/64331 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 木原 章雄
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