Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3β/β-catenin axis activation.

Abstract

Peritoneal fibrosis is a severe complication arising from long-term peritoneal dialysis (PD). Tamoxifen (Tamo) has been clinically proven effective in a series of fibrotic diseases, such as PD-associated encapsulating peritoneal sclerosis (EPS), but the mechanisms underlying Tamoxifen's protective effects are yet to be defined. In the present study, C57BL/6 mice received intraperitoneal injections of either saline, 4.25% high glucose (HG) PD fluid (PDF) or PDF plus Tamoxifen each day for 30 days. Tamoxifen attenuated thickening of the peritoneum, and reversed PDF-induced peritoneal expression of E-cadherin, Vimentin, matrix metalloproteinase 9 (MMP9), Snail, and β-catenin. Mouse peritoneal mesothelial cells (mPMCs) were cultured in 4.25% glucose or 4.25% glucose plus Tamoxifen for 48 h. Tamoxifen inhibited epithelial-to-mesenchymal transition (EMT) as well as phosphorylation of glycogen synthase kinase-3β (GSK-3β), nuclear β-catenin, and Snail induced by exposure to HG. TWS119 reversed the effects of Tamoxifen on β-catenin and Snail expression. In conclusion, Tamoxifen significantly attenuated EMT during peritoneal epithelial fibrosis, in part by inhibiting GSK-3β/β-catenin activation.

• Authors: Pengpeng Yan, Huanna Tang, Xiaoying Chen, Shuiyu Ji, Wei Jin, Jiaming Zhang, Jia Shen, Hao Deng, Xiang Zhao, Quanquan Shen, Hongfeng Huang
• Journal: Bioscience reports (Biosci Rep) Vol. 38 Issue 6 (12 21 2018) ISSN: 1573-4935 [Electronic] England
• PMID: 30061174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Author(s).

Chemical References

• CTNNB1 protein, mouse
• Pyrimidines
• Pyrroles
• Snai1 protein, mouse
• Snail Family Transcription Factors
• TWS 119
• beta Catenin
• Tamoxifen
• Glycogen Synthase Kinase 3 beta
• Matrix Metalloproteinase 9
• Glucose

Topics

• Animals
• Disease Models, Animal
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Expression Regulation (drug effects)
• Glucose (administration & dosage)
• Glycogen Synthase Kinase 3 beta (genetics)
• Humans
• Matrix Metalloproteinase 9 (genetics)
• Mice
• Peritoneal Dialysis (adverse effects)
• Peritoneal Fibrosis (drug therapy, etiology, genetics, pathology)
• Peritoneum (drug effects, pathology)
• Phosphorylation (drug effects)
• Pyrimidines (administration & dosage)
• Pyrroles (administration & dosage)
• Snail Family Transcription Factors (genetics)
• Tamoxifen (administration & dosage)
• beta Catenin (genetics)