Wnt/beta-catenin 信号通路在腹膜透析腹膜间皮细胞转分化中的作用及机制研究

Peritoneal dialysis (PD) is an attractive treatment for patients with end-stage renal disease (ESRD). However, continuously exposure to non-physiological peritoneal dialysis solution (PDS), it will inevitably lead to peritoneal fibrosis, which ultimately cause to ultrafiltration failure and increased morbidity as well as mortality. The establishment of peritoneal fibrosis has been associated with the epithelial to mesenchymal transition (EMT) of the peritoneal mesothelial cells monolayerMany cytokines and pathways were found take part in this process, however, the molecular mechanism is still not well defined yet and no effective treatment has been found...In recent years, the role of Wnt/β-catenin signaling in regulating EMT during organ fibrosis and tumor metastasis has been established. Therefore, we hypothesize that Wnt/β-catenin signaling maybe involve in the progression of peritoneal dialysis induced peritoneal mesothelial cells EMT and peritoneal fibrosis. To this end, experimental research is carried out as follow: 1. Whether Wnt/beta-catenin signaling is activited in the peritoneal mesothelial cells isolated from peritoneal dialysis effluents 2. The role of Wnt/beta-catenin signaling in high glucose induced epithelial-mesenchymal transition of human peritoneal mesothelial cells 3.Effect of ICG-001 in inhibiting the progression of EMT of human peritonal mesothelial cells

长期接受腹膜透析（PD）的患者常出现腹膜纤维化而降低透析效能，其中腹膜间皮细胞转分化（EMT）在其中起到关键作用，但其发生机制尚不明确。近年来的研究显示，Wnt/β-catenin信号通路的异常活化与许多疾病，如肿瘤、遗传性疾病和器官纤维化等相关，并己证明其参与多种细胞EMT及器官纤维化的发生。根据文献，我们提出“Wnt/beta-catenin信号通路在腹膜间皮细胞转分化中起到重要作用，阻断该信号可抑制腹膜间皮细胞转分化的进展”的假说，并计划观察：1.长期透析患者腹膜间皮细胞Wnt/beta-catenin信号活化 2.Wnt/beta-catenin 信号在腹膜间皮细胞转分化中的作用 3.评估小分子抑制剂ICG-001靶向抑制beta-catenin对腹膜间皮细胞转分化的干预作用。腹膜透析室重要的肾脏替代治疗方式，如上述假说能被验证，将为防止、延缓腹膜透析腹膜纤维化的发生提供新的思路。

腹膜透析腹膜纤维化是导致超滤衰竭的重要因素，在临床实践中仍是一个重要的挑战，其中腹膜间皮细胞转分化被认为起到关键的作用，但是其具体发生机制仍不明确。近年来，Wnt/β-catenin 信号通路的异常活化与许多疾病，如肿瘤、遗传性疾病和器官纤维化等相关，并己证明其参与多种细胞EMT及器官纤维化的发生。因此，我们探讨其是否在腹膜透析纤维中起到重要作用。我们分离腹膜透析患者腹透液中的腹膜间皮细胞，发现与透析1月内患者相比，透析一年以上患者Wnt1, Wnt5a, β-catenin, LEF1表达显著升高，并且这种变化伴随着腹膜间皮细胞转分化的发生。此外，我们应用高糖刺激腹膜间皮细胞株，发现Wnt1, Wnt5a, β-catenin, LEF1表达升高，且这种变化能被Wnt/β-catenin 信号抑制剂DKK1所部分阻断。最后我们建立腹膜透析小鼠模型，发现腹膜透析液能够导致小鼠腹膜β-catenin的明显升高，且此过程可被Wnt/β-catenin的小分子抑制剂ICG-001部分逆转。因此，这些数据提示Wnt/β-catenin信号通路在腹膜透析所致转分化及纤维化过程中起到重要作用，其可能成为一个潜在治疗靶点。