ADAM19/Notch1调控腹膜间皮细胞与单核/巨噬细胞交互应答致腹膜纤维化的机制研究

腹膜透析（PD）是终末期肾病主要的替代治疗方式之一，长期生存率亟待提高。腹膜纤维化造成腹膜失功，严重影响患者生活质量和生存，目前机制未明。ADAM19是调控炎症与发育重要的膜蛋白。我们前期研究发现，在腹膜炎症及纤维化模型中，ADAM19可以在腹膜间皮细胞和单核/巨噬细胞中表达上调；单核/巨噬细胞特异性敲除ADAM19后，小鼠炎症水平降低；同时ADAM19可以切割Notch1，激活Notch下游通路。由此，我们提出：PD腹膜组织长期炎症微环境可以刺激腹膜间皮细胞和单核/巨噬细胞表达ADAM19，引起腹膜间皮细胞向成纤维细胞转分化和单核/巨噬细胞活化与浸润，协同促进炎症级联反应，导致纤维化发生。本研究拟进一步利用体外细胞及ADAM19 CKO小鼠模型，观察ADAM19/Notch1对腹膜间皮细胞和单核/巨噬细胞功能的调控及细胞相互作用；并验证ADAM19作为生物标记物预测腹膜纤维化的可行性。

Peritoneal dialysis (PD) is one of the main renal replacement therapies for end-stage renal disease, and the long-term survival urgently needs to be improved. Peritoneal fibrosis causes peritoneal function failure, which seriously affects the life quality and survival of PD patients. However, the mechanism remains unknown. ADAM19 is an important membrane protein that regulates inflammation and development. Our previous work revealed that ADAM19 was expressed in peritoneal mesothelial cells and monocytes/macrophages during the development of peritoneal inflammation and fibrosis. Treated ADAM19fl/fl;Lyz2-Cre mice with LPS, the level of inflammation was reduced compared with wide type mice. Meanwhile, ADAM19 could activate Notch signaling by Notch1 cleavage. On this basis, we raise the hypothesis that the long-term inflammatory milieu of peritoneum in PD patients can stimulate the expression of ADAM19 on peritoneal mesothelial cells and monocytes/macrophages, causing the peritoneal mesothelial cells to fibroblasts transition and the activation and infiltration of monocytes/macrophages, thereby promoting the inflammatory cascade, and leading to peritoneal fibrosis eventually. We intend to further observe the regulation of ADAM19/Notch1 on peritoneal mesothelial cells and monocytes/macrophages and cross-talk between these two cells by in vitro cells and ADAM19fl/fl; Lyz2-Cre CKO mouse models, and verify the possibility of ADAM19 as a biomarker to predict peritoneal fibrosis meanwhile. We will clarify the role of ADAM19/Notch1 pathway on peritoneal fibrosis and provide potential new targets for clinical intervention.