Abstract：
Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.
摘要：
腹膜透析是终末期肾病的常用治疗方法,但并发症往往迫使其停止。目前缺乏针对腹膜炎症和纤维化的预防性治疗。Cyclo（His-Pro）（CHP），一种天然存在的环状二肽，在各种纤维化疾病中表现出保护作用，然而,其在腹膜纤维化(PF)中的潜在作用仍不确定.在诱导PF的小鼠模型中，卫生防护中心被管理，采用液相色谱-串联质谱法进行定量蛋白质组学分析，以鉴定PF相关蛋白信号通路。使用人原代培养的间皮细胞进一步验证结果。该分析揭示了组蛋白脱乙酰酶3（HDAC3）参与PF信号通路。CHP给药可有效减轻腹膜组织和人原代培养的间皮细胞中的PF，同时调节纤维化相关标志物和HDAC3表达。此外，CHP增强核因子红细胞相关因子2（Nrf2）的表达，同时抑制叉头框蛋白M1（FOXM1），已知通过与HDAC3的相互作用抑制Nrf2转录。CHP还显示对脾骨髓来源的抑制细胞的影响，表明有免疫调节作用.值得注意的是,CHP改善腹膜组织线粒体功能，导致线粒体膜电位增加和三磷酸腺苷的产生。这项研究表明，CHP可以通过调节HDAC3表达和相关信号通路来显著预防腹膜透析患者的PF，减少纤维化和炎症标志物，改善线粒体功能。
