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.
Cell Line
Epithelial Cells
/ drug effects
Epithelial-Mesenchymal Transition
/ drug effects
Fibrosis
Humans
Kidney Diseases
/ chemically induced
Kidney Tubules
/ drug effects
Phosphorylation
Protective Agents
/ pharmacology
Smad2 Protein
/ metabolism
Smad3 Protein
/ metabolism
Transforming Growth Factor beta1
/ toxicity
Wnt Signaling Pathway
/ drug effects
TGF-β1/SMAD signalling
WNT/β-catenin inhibitor
renal fibrosis
tubular epithelial cells
Journal
Clinical and experimental pharmacology & physiology
ISSN: 1440-1681
Titre abrégé: Clin Exp Pharmacol Physiol
Pays: Australia
ID NLM: 0425076
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
26
03
2019
revised:
03
12
2019
accepted:
29
01
2020
pubmed:
6
2
2020
medline:
14
7
2021
entrez:
4
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32012313
doi: 10.1111/1440-1681.13270
doi:
Substances chimiques
Protective Agents
0
SMAD2 protein, human
0
SMAD3 protein, human
0
Smad2 Protein
0
Smad3 Protein
0
Transforming Growth Factor beta1
0
Types de publication
Comparative Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
940-946Informations de copyright
© 2020 John Wiley & Sons Australia, Ltd.
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