Liu Feng, Yu Chao, Qin Huan, Zhang Shenglei, Fang Lu, Wang Yi, Wang Jun, Cui Binbin, Hu Susie, Liu Na, Zhuang Shougang
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
J Cell Mol Med. 2021 May 5;25(13):6103-14. doi: 10.1111/jcmm.16518.
Nintedanib, an Food and Drug Administration (FDA) approved multiple tyrosine kinase inhibitor, exhibits an anti-fibrotic effect in lung and kidneys. Its effect on peritoneal fibrosis remains unexplored. In this study, we found that nintedanib administration lessened chlorhexidine gluconate (CG)-induced peritoneal fibrosis and reduced collagen I and fibronectin expression. This coincided with suppressed phosphorylation of platelet-derived growth factor receptor, fibroblast growth factor receptors, vascular endothelial growth factor receptor and Src family kinase. Mechanistically, nintedanib inhibited injury-induced mesothelial-to-mesenchymal transition (MMT), as demonstrated by decreased expression of α-smooth muscle antigen and vimentin and preserved expression of E-cadherin in the CG-injured peritoneum and cultured human peritoneal mesothelial cells exposed to transforming growth factor-β1. Nintedanib also suppressed expression of Snail and Twist, two transcription factors associated with MMT in vivo and in vitro. Moreover, nintedanib treatment inhibited expression of several cytokines/chemokines, including tumour necrosis factor-α, interleukin-1β and interleukin-6, monocyte chemoattractant protein-1 and prevented infiltration of macrophages to the injured peritoneum. Finally, nintedanib reduced CG-induced peritoneal vascularization. These data suggest that nintedanib may attenuate peritoneal fibrosis by inhibiting MMT, inflammation, and angiogenesis and have therapeutic potential for the prevention and treatment of peritoneal fibrosis in patients on peritoneal dialysis.
尼达尼布是一种经美国食品药品监督管理局（FDA）批准的多靶点酪氨酸激酶抑制剂，在肺和肾脏中具有抗纤维化作用。其对腹膜纤维化的影响尚未得到研究。在本研究中，我们发现给予尼达尼布可减轻葡萄糖酸氯己定（CG）诱导的腹膜纤维化，并降低Ⅰ型胶原蛋白和纤连蛋白的表达。这与血小板衍生生长因子受体、成纤维细胞生长因子受体、血管内皮生长因子受体和Src家族激酶的磷酸化受到抑制相一致。机制上，尼达尼布抑制损伤诱导的间皮-间充质转化（MMT），这在CG损伤的腹膜和暴露于转化生长因子-β1的培养人腹膜间皮细胞中表现为α-平滑肌肌动蛋白和波形蛋白表达降低，而E-钙黏蛋白表达得以保留。尼达尼布还抑制了Snail和Twist的表达，这两种转录因子在体内和体外均与MMT相关。此外尼达尼布治疗抑制了几种细胞因子/趋化因子的表达，包括肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6、单核细胞趋化蛋白-1，并阻止巨噬细胞浸润到损伤的腹膜。最后，尼达尼布减少了CG诱导的腹膜血管生成。这些数据表明，尼达尼布可能通过抑制MMT、炎症和血管生成来减轻腹膜纤维化，对预防和治疗腹膜透析患者的腹膜纤维化具有治疗潜力。
