Shi Yingfeng, Hu Yan, Wang Yi, Ma Xiaoyan, Tang Lunxian, Tao Min, Qiu Andong, Zhuang Shougang, Liu Na
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Emergency Department of Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Front Pharmacol. 2021 Aug 23;12:724141. doi: 10.3389/fphar.2021.724141. eCollection 2021.
Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome . Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect and . These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.
腹膜纤维化（PF）是长期腹膜透析（PD）患者超滤失败的主要原因。然而，已证明有限的措施对PF的预防和治疗有效。一些观点表明自噬的激活可改善PF，但另一些观点则表明自噬会促进PF。显然，自噬在PF中的作用存在争议，需要进一步研究。在此，我们研究了自噬在PF大鼠模型和受损的人腹膜间皮细胞（HPMC）培养物中的作用。在由4.25%腹膜透析液（PDF）和0.1%葡萄糖酸氯己定（CG）诱导的两种PF大鼠模型的纤维化腹膜中，自噬被高度激活。用3-甲基腺嘌呤（3-MA）阻断自噬可有效预防两种模型中的PF，并通过下调TGF-β/Smad3信号通路及下游核转录因子Slug和Snail来逆转上皮-间质转化（EMT）。用3-MA治疗还可抑制PF期间EGFR/ERK1/2信号通路的激活。此外，3-MA显著降低STAT3/NF-κB介导的炎症反应和巨噬细胞浸润，并通过下调β-连环蛋白信号来预防腹膜血管生成。此外，TGF-β1刺激上调了自噬活性，自噬体增加证明了这一点。将HPMC暴露于TGF-β1会导致EMT的诱导以及TGF-β/Smad3、EGFR/ERK1/2信号通路的激活。用3-MA治疗可阻断所有这些反应。此外，延迟给予3-MA可有效减少由TGF-β1诱导的EMT。综上所述，我们的研究表明自噬可能促进PF，而3-MA具有抗纤维化作用。这些结果表明，自噬可能是长期PD临床患者PF治疗的潜在靶点。
