Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Clin Sci (Lond). 2021 Jan 15;135(1):53-69. doi: 10.1042/CS20201038.
Chronic allograft dysfunction is a major cause of late graft failure after kidney transplantation. One of the histological changes is interstitial fibrosis, which is associated with epithelial-mesenchymal transition. Bortezomib has been reported to prevent the progression of fibrosis in organs. We used rat renal transplantation model and human kidney 2 cell line treated with tumor necrosis factor-α (TNF-α) to examine their response to bortezomib. To explore the mechanism behind it, we assessed the previously studied TNF-α/protein kinase B (Akt)/Smad ubiquitin regulatory factor 2 (Smurf2) signaling and performed RNA sequencing. Our results suggested that bortezomib could attenuate the TNF-α-induced epithelial-mesenchymal transition and renal allograft interstitial fibrosis in vitro and in vivo. In addition to blocking Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase/Smurf2 signaling, bortezomib's effect on the epithelial-mesenchymal transition was associated with inhibition of nuclear factor kappa B (NF-κB) pathway by stabilizing inhibitor of NF-κB. The study highlighted the therapeutic potential of bortezomib on renal allograft interstitial fibrosis. Such an effect may result from inhibition of NF-κB/TNF-α/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of inhibitor of NF-κB.
慢性移植物功能障碍是肾移植后晚期移植物失功的主要原因之一。组织学变化之一是间质纤维化，其与上皮-间充质转化有关。硼替佐米已被报道可预防器官纤维化的进展。我们使用大鼠肾移植模型和人肾 2 细胞系（TNF-α）处理来检测硼替佐米的反应。为了探讨其背后的机制，我们评估了先前研究的 TNF-α/蛋白激酶 B（Akt）/Smad 泛素调节因子 2（Smurf2）信号，并进行了 RNA 测序。我们的结果表明，硼替佐米可减轻 TNF-α 诱导的体外和体内上皮-间充质转化和肾移植间质纤维化。除了阻断 Akt/哺乳动物雷帕霉素靶蛋白（mTOR）/p70S6 激酶/Smurf2 信号外，硼替佐米对上皮-间充质转化的作用与通过稳定 NF-κB 抑制剂来抑制核因子 κB（NF-κB）途径有关。该研究强调了硼替佐米在肾移植间质纤维化中的治疗潜力。这种作用可能是通过稳定 NF-κB 抑制剂来抑制 NF-κB/TNF-α/Akt/mTOR/p70S6 激酶/Smurf2 信号而产生的。
