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

Pengpeng Yan,Hongfeng Huang,Huanna Tang,Jia Shen,Xiaoying Chen,Jiaming Zhang,Quanquan Shen,Shuiyu Ji,Hao Deng,Xiang Zhao,Wei Jin

doi:10.1042/bsr20180240

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.

Highlights

Peritoneal dialysis (PD) is a cost-effective renal replacement therapy for end-stage renal disease (ESRD) [1]
We examined the effects of Tamoxifen on epithelial-to-mesenchymal transition (EMT) during high glucose (HG)-induced fibrosis in a C57BL/6 mouse model, on cultured mouse peritoneal mesothelial cells (PMCs) exposed to HG and on glycogen synthase kinase-3β (GSK-3β)/β-catenin axis stimulation
EMT process was enhanced in PD fluid (PDF) treated peritoneal membrane and HG treated mouse peritoneal mesothelial cell (mPMC)

Summary

Introduction

Peritoneal dialysis (PD) is a cost-effective renal replacement therapy for end-stage renal disease (ESRD) [1]. The pathological process involves myofibroblast generation from epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs), contributing to increased rates of peritoneal transport and peritoneal fibrosis [4,5,6]. Tamoxifen is a selective estrogen receptor modulator initially used for the treatment of breast cancer [11] It displays anti-fibrotic activity in disorders such as retroperitoneal fibrosis [12], encapsulating peritoneal sclerosis (EPS) [13], sclerosing mesenteritis [14], sclerosing cervicitis, and fibrosing mediastinitis [15]. Tamoxifen’s anti-fibrosis activity has been linked to inhibition of contributing pathological processes including EMT and angiogenesis [6] and connective tissue growth factor promotion of collagen synthesis [16], and stimulation of metalloproteinase-9 degradation of collagen [17].

Methods

Results

Conclusion