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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)

Submitter: 木原 章雄

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