WNT/β‐catenin signal inhibitor IC‐2–derived small‐molecule compounds suppress TGF‐β1–induced fibrogenic response of renal epithelial cells by inhibiting SMAD2/3 signalling
| العنوان: | WNT/β‐catenin signal inhibitor IC‐2–derived small‐molecule compounds suppress TGF‐β1–induced fibrogenic response of renal epithelial cells by inhibiting SMAD2/3 signalling |
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| المؤلفون: | Hiroyuki Oka, Hiroyuki Tsuchiya, Tomoaki Takata, Minoru Morimoto, Noriko Itaba, Goshi Shiota, Kyosuke Suzuki, Shotaro Hoi, Hajime Isomoto |
| المصدر: | Clinical and Experimental Pharmacology and Physiology. 47:940-946 |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Epithelial-Mesenchymal Transition, Physiology, Smad2 Protein, SMAD, Protective Agents, Cell Line, Transforming Growth Factor beta1, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Renal fibrosis, medicine, Humans, Smad3 Protein, Phosphorylation, Wnt Signaling Pathway, Pharmacology, Hepatocyte differentiation, Chemistry, Wnt signaling pathway, Epithelial Cells, medicine.disease, Fibrosis, Kidney Tubules, 030104 developmental biology, 030220 oncology & carcinogenesis, Catenin, Cancer research, Kidney Diseases, Signal transduction, Kidney disease, Transforming growth factor |
| الوصف: | Renal fibrosis compromises kidney function, and it is a risk factor for chronic kidney disease (CKD). CKD ultimately progresses to end-stage kidney disease that can be cured only by kidney transplantation. Owing to the increasing number of CKD patients, effective treatment strategies are urgently required for renal fibrosis. TGF-β is a well-established fibrogenic factor that signals through SMAD2/3 signaling pathway. It was shown that there is a cross-talk between TGF-β/SMAD and WNT/β-catenin signaling pathways in renal tubular epithelial cells, and that a WNT/β-catenin inhibitor, ICG-001, ameliorates TGF-β1induced renal fibrosis. IC-2, a derivative of ICG-001, has been shown to potently induce hepatocyte differentiation of human mesenchymal stem cells by inhibiting WNT/β-catenin signaling. In the present study, we examined the effect of ICG-001, IC-2, and IC-2 derivatives (IC-2-506-1, IC-2-506-2, IC-2-506-3, IC-2-Ar-Cl, IC-2-OH, IC-2-OTBS, and IC-2-F) on TGF-β1-induced SMAD activation and fibrogenic response in immortalized human renal tubular epithelial HK-2 cells. All these compounds inhibited LiCl-induced WNT/β-catenin reporter activation to a similar extent, whereas ICG-001, IC-2-OTBS, and IC-2-F almost completely suppressed TGF-β1-induced SMAD reporter activation without apparent cytotoxicity. Phosphorylation of SMAD2/3 by TGF-β1 was more potently inhibited by IC-2-OTBS and IC-2-F than by ICG-001 and IC-2. IC-2-F suppressed TGF-β1-induced COL1A1 protein expression, whereas IC-2-506-1 and IC-2-OTBS suppressed TGF-β1-induced epithelial-mesenchymal transition. These results demonstrated that IC-2 derivatives suppress the TGF-β1-induced fibrogenic response of tubular epithelial cells and thus could be promising therapeutic agents for the treatment of renal fibrosis. |
| تدمد: | 1440-1681 0305-1870 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::63baab6b406306a87120449dfbc5d77c https://doi.org/10.1111/1440-1681.13270 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....63baab6b406306a87120449dfbc5d77c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14401681 03051870 |
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