Bortezomib attenuates renal interstitial fibrosis in kidney transplantation via regulating the EMT induced by TNF-α-Smurf1-Akt-mTOR-P70S6K pathway
Bortezomib attenuates renal interstitial fibrosis in kidney transplantation via regulating the EMT induced by TNF-α-Smurf1-Akt-mTOR-P70S6K pathway
复制标题
硼替佐米通过调节 TNF–α–Smurf1–Akt–mTOR–P70S6K 通路诱导的 EMT 减轻肾移植中的肾间质纤维化
DOI：
10.1111/jcmm.14420
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发表时间：
2019-08-01
影响因子：
5.3
通讯作者：
Tan, Ruoyun
中科院分区：
文献类型：
--
作者：
Zhou, Jiajun;Cheng, Hong;Tan, Ruoyun
同种异体移植物间质纤维化的特征是由活化的成纤维细胞和肌成纤维细胞引起的大量细胞外基质沉积。上皮-间质转化（EMT）被认为是肌成纤维细胞的重要来源，有助于同种异体移植间质纤维化的发病机制。Smadubiquitination regulatory factor 1（Smurf 1）参与了EMT的发生发展。本研究旨在探讨硼替佐米和Smurf 1在移植物间质纤维化和EMT中的作用。通过蛋白质印迹或qRT-PCR，在以不同剂量或在不同时间点用肿瘤坏死因子α（TNF-α）处理的人近端肾小管上皮细胞（HK-2）中检查EMT的生物标志物以及Smurf 1。我们在HK-2细胞中敲低或过表达Smurf 1。建立大鼠肾移植模型，并给予硼替佐米干预。同时收集人和大鼠的同种异体移植组织，进行HE、Masson三色染色、免疫组织化学染色和蛋白质印迹分析。结果发现，TNF-α通过Smurf 1/Akt/mTOR/P70 S6 K信号通路以时间依赖和剂量依赖的方式显著促进EMT的发生。更重要的是，硼替佐米通过抑制TNF-α的产生和Smurf 1的表达，在体内和体外缓解EMT和同种异体移植物间质纤维化的进展。总之，Smurf 1在TNF-α诱导的EMT的发展中起着关键作用。硼替佐米可抑制Sumrf 1介导的EMT和移植肾间质纤维化的进展，有望成为防治移植肾间质纤维化的新选择。
Allograft interstitial fibrosis was characterized by massive extracellular matrix deposition caused by activated fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) is recognized as an important source of myofibroblasts contributing to the pathogenesis of allograft interstitial fibrosis. Smad ubiquitination regulatory factor 1 (Smurf1) has been recently reported to be involved in the progression of EMT. Our study was to detect the effect of Bortezomib and Smurf1 in the EMT and allograft interstitial fibrosis. Biomarkers of EMT, as well as Smurf1, were examined in human proximal tubular epithelial cells (HK-2) treated with tumour necrosis factoralpha (TNF-alpha) in various doses or at various time points by Western Blotting or qRT-PCR. We knockdown or overexpressed Smurf1 in HK-2 cells. Furthermore, rat renal transplant model was established and intervened by Bortezomib. Allograft tissues from human and rats were also collected and prepared for HE, Masson's trichrome, immunohistochemical staining and western blotting assays. As a result, we found that TNF-alpha significantly promoted the development of EMT in a time-dependent and dose-dependent manner through Smurf1/Akt/mTOR/P70S6K signalling pathway. More importantly, Bortezomib alleviated the progression of EMT and allograft interstitial fibrosis in vivo and in vitro by inhibiting the production of TNF-alpha and expression of Smurf1. In conclusion, Smurf1 plays a critical role in the development of EMT induced by TNF-alpha. Bortezomib can attenuate the Sumrf1-mediated progression of EMT and renal allograft interstitial fibrosis, which could be suggested as a novel choice for the prevention and treatment of renal allograft interstitial fibrosis.