Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK3β/β-catenin axis activation
Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK3β/β-catenin axis activation
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他莫昔芬通过抑制 GSK3β/β-连环蛋白轴激活来减轻透析液诱导的腹膜纤维化
DOI：
10.1042/bsr20180240
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Hongfeng Huang
中科院分区：
文献类型：
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作者：
Pengpeng Yan;Huanna Tang;Xiaoying Chen;Shuiyu Ji;Wei Jin;Jiaming Zhang;Jia Shen;Hao Deng;Xiang Zhao;Quanquan Shen;Hongfeng Huang
腹膜纤维化是长期腹膜透析（PD）的严重并发症。他莫昔芬（Tamoxifen，Tamo）已被临床证实对一系列纤维化疾病有效，如PD相关的包裹性腹膜硬化症（EPS），但他莫昔芬保护作用的机制尚未确定。在本研究中，C57 BL/6小鼠每天接受生理盐水、4.25%高葡萄糖（HG）PD液（PDF）或PDF加他莫昔芬的腹膜内注射，持续30天。他莫昔芬减轻了腹膜增厚，逆转了PDF诱导的E-钙粘蛋白、波形蛋白、基质金属蛋白酶9（MMP 9）、Snail和β-连环蛋白的腹膜表达。将小鼠腹膜间皮细胞（mPMC）在4.25%葡萄糖或4.25%葡萄糖加他莫昔芬中培养48小时。他莫昔芬抑制暴露于HG诱导的上皮-间质转化（EMT）以及糖原合成酶激酶-3 β（GSK-3β）、核β-连环蛋白和Snail的磷酸化。TWS 119逆转了他莫昔芬对β-catenin和Snail表达的影响。总之，他莫昔芬显著减弱腹膜上皮纤维化期间的EMT，部分是通过抑制GSK-3β/β-catenin活化。
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.