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.
Int J Mol Sci. 2021 Apr 29;22(9):4739. doi: 10.3390/ijms22094739.
We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-β treatment, but these changes were attenuated by cotreatment with GW788388. TGF-β-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-β and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-β receptor type 1 inhibitor, effectively attenuated TGF-β-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.
我们研究了转化生长因子β-1（TGF-β）受体抑制剂 GW788388 对人腹膜间皮细胞（HPMCs）上皮间质转化（EMT）的作用，并使用腹膜纤维化小鼠模型研究了 GW788388 对腹膜的作用。用 TGF-β处理 HPMCs，并用或不用 GW788388 进行处理。动物实验在雄性 C57/BL6 小鼠上进行。用葡萄糖酸氯己定腹腔内注射诱导腹膜纤维化。GW788388 通过每日一次口服灌胃给药。TGF-β处理导致 HPMCs 的形态变化、细胞迁移和侵袭，但这些变化通过与 GW788388 共同处理而减弱。TGF-β处理的 HPMCs 降低了上皮细胞标志物的水平，增加了间充质细胞标志物的水平。与 GW788388 共同处理逆转了这些变化。磷酸化 Smad2 和 Smad3 蛋白水平被 TGF-β刺激，与 GW788388 共同处理减弱了这种变化。对于腹膜纤维化小鼠，壁层腹膜的厚度和胶原沉积增加，但与 GW788388 共同处理减轻了这种变化。GW788388 是一种口服有效的强效 TGF-β 受体 1 抑制剂，可有效减轻 HPMCs 中 TGF-β诱导的 EMT。GW788388 共同处理改善了腹膜厚度和纤维化，并在腹膜纤维化小鼠模型中恢复了腹膜功能。
