AM251 Suppresses Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells
| Autor: | Kenichi Higashino, Akio Kihara, Toru Nakano, Yoshito Numata, Tomoyo Yoshinaga, Shoichi Naito, Ken-Ichiro Uwabe |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell signaling Microarrays Gene Expression lcsh:Medicine Artificial Gene Amplification and Extension SMAD Signal transduction Polymerase Chain Reaction Epithelium Piperidines Animal Cells Medicine and Health Sciences lcsh:Science Cell Line Transformed Multidisciplinary Chemistry Signaling cascades Bioassays and Physiological Analysis Kidney Tubules Cellular Types Anatomy Research Article Cell biology MAPK signaling cascades Epithelial-Mesenchymal Transition JUNB Library Screening Research and Analysis Methods 03 medical and health sciences Downregulation and upregulation Genetics Humans Epithelial–mesenchymal transition Molecular Biology Techniques Protein kinase A Molecular Biology Molecular Biology Assays and Analysis Techniques Biology and life sciences lcsh:R Epithelial Cells Reverse Transcriptase-Polymerase Chain Reaction Fibrosis Biological Tissue 030104 developmental biology TGF-beta signaling cascade Cancer research Pyrazoles lcsh:Q Developmental Biology Transforming growth factor |
| Zdroj: | PLoS ONE, Vol 11, Iss 12, p e0167848 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|