Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Nephrology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
J Cell Mol Med. 2018 Feb;22(2):1190-1201. doi: 10.1111/jcmm.13393. Epub 2017 Oct 27.
Long-term peritoneal dialysis is accompanied by functional and histopathological alterations in the peritoneal membrane. In the long process of peritoneal dialysis, high-glucose peritoneal dialysis solution (HGPDS) will aggravate the peritoneal fibrosis, leading to decreased effectiveness of peritoneal dialysis and ultrafiltration failure. In this study, we found that the coincidence of elevated TGF-β1 expression, autophagy, apoptosis and fibrosis in peritoneal membrane from patients with peritoneal dialysis. The peritoneal membranes from patients were performed with immunocytochemistry and transmission electron microscopy. Human peritoneal mesothelial cells were treated with 1.5%, 2.5% and 4.25% HGPDS for 24 hrs; Human peritoneal mesothelial cells pre-treated with TGF-β1 (10 ng/ml) or transfected with siRNA Beclin1 were treated with 4.25% HGPDS or vehicle for 24 hrs. We further detected the production of TGF-β1, activation of TGF-β1/Smad2/3 signalling, induction of autophagy, EMT, fibrosis and apoptosis. We also explored whether autophagy inhibition by siRNA targeting Beclin 1 reduces EMT, fibrosis and apoptosis in human peritoneal mesothelial cells. HGPDS increased TGF-β1 production, activated TGF-β1/Smad2/3 signalling and induced autophagy, fibrosis and apoptosis hallmarks in human peritoneal mesothelial cells; HGPDS-induced Beclin 1-dependent autophagy in human peritoneal mesothelial cells; Autophagy inhibition by siRNA Beclin 1 reduced EMT, fibrosis and apoptosis in human peritoneal mesothelial cells. Taken all together, these studies are expected to open a new avenue in the understanding of peritoneal fibrosis, which may guide us to explore the compounds targeting autophagy and achieve the therapeutic improvement of PD.
长期腹膜透析伴随着腹膜功能和组织病理学的改变。在长期腹膜透析过程中，高糖腹膜透析液（HGPDS）会加重腹膜纤维化，导致腹膜透析效果下降和超滤失败。在这项研究中，我们发现腹膜透析患者腹膜中 TGF-β1 表达升高、自噬、凋亡和纤维化的同时存在。对腹膜透析患者的腹膜进行免疫细胞化学和透射电子显微镜检查。用 1.5%、2.5%和 4.25% HGPDS 处理人腹膜间皮细胞 24 小时；用 TGF-β1（10ng/ml）预处理人腹膜间皮细胞或用 Beclin1 siRNA 转染后，用 4.25% HGPDS 或载体处理 24 小时。我们进一步检测 TGF-β1 的产生、TGF-β1/Smad2/3 信号通路的激活、自噬的诱导、上皮间质转化（EMT）、纤维化和凋亡。我们还探讨了靶向 Beclin1 的 siRNA 是否通过抑制自噬减少人腹膜间皮细胞中的 EMT、纤维化和凋亡。HGPDS 增加了 TGF-β1 的产生，激活了 TGF-β1/Smad2/3 信号通路，并诱导了人腹膜间皮细胞的自噬、纤维化和凋亡特征；HGPDS 诱导了人腹膜间皮细胞中 Beclin1 依赖性自噬；siRNA Beclin1 抑制自噬减少了人腹膜间皮细胞中的 EMT、纤维化和凋亡。总之，这些研究有望为理解腹膜纤维化开辟新途径，为探索靶向自噬的化合物和实现 PD 的治疗改善提供指导。
