Heo Jung-Yoon, Do Jun-Young, Lho Yunmee, Kim A-Young, Kim Sang-Woon, Kang Seok-Hui
Department of Internal Medicine, Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu 42415, Korea.
Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea.
Biomedicines. 2021 Jul 19;9(7):839. doi: 10.3390/biomedicines9070839.
We investigated the effect of SB525334 (TGFβ receptor type 1 (TβRI) inhibitor) on the epithelial to mesenchymal transition (EMT) signaling pathway in human peritoneal mesothelial cells (HPMCs) and a peritoneal fibrosis mouse model. In vitro experiments were performed using HPMCs. HPMCs were treated with TGFβ1 and/or SB525334. In vivo experiments were conducted with male C57/BL6 mice. The 0.1% chlorhexidine gluconate (CG) was intraperitoneally injected with or without SB52534 administration by oral gavage. Mice were euthanized after 28 days. EMT using TGFβ1-treated HPMCs included morphological changes, cell migration and invasion, EMT markers and collagen synthesis. These pathological changes were reversed by co-treatment with SB525334. CG injection was associated with an increase in peritoneal fibrosis and thickness, which functionally resulted in an increase in the glucose absorption via peritoneum. Co-treatment with SB525334 attenuated these changes. The levels of EMT protein markers and immunohistochemical staining for fibrosis showed similar trends. Immunofluorescence staining for EMT markers showed induction of transformed cells with both epithelial and mesenchymal cell markers, which decreased upon co-treatment with SB525334. SB525334 effectively attenuated the TGF-β1-induced EMT in HPMCs. Cotreatment with SB525334 improved peritoneal thickness and fibrosis and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.
我们研究了SB525334（转化生长因子β1型受体（TβRI）抑制剂）对人腹膜间皮细胞（HPMCs）上皮-间质转化（EMT）信号通路及腹膜纤维化小鼠模型的影响。使用HPMCs进行体外实验。用转化生长因子β1（TGFβ1）和/或SB525334处理HPMCs。用雄性C57/BL6小鼠进行体内实验。腹腔注射0.1%葡萄糖酸氯己定（CG），同时或不通过灌胃给予SB52534。28天后对小鼠实施安乐死。TGFβ1处理的HPMCs发生的EMT包括形态学改变、细胞迁移和侵袭、EMT标志物及胶原蛋白合成。与SB525334联合处理可逆转这些病理变化。注射CG与腹膜纤维化及厚度增加相关，其功能上导致经腹膜的葡萄糖吸收增加。与SB525334联合处理可减轻这些变化。EMT蛋白标志物水平及纤维化的免疫组化染色显示出相似趋势。EMT标志物的免疫荧光染色显示同时具有上皮和间充质细胞标志物的转化细胞的诱导，与SB525334联合处理后这种诱导减少。SB525334有效减轻了TGF-β1诱导的HPMCs中的EMT。在腹膜纤维化小鼠模型中，与SB525334联合处理改善了腹膜厚度和纤维化，并恢复了腹膜功能。
