硝基油酸对腹膜纤维化的干预作用及机制的研究

Peritoneal dialysis (PD) is an effective and affordable form of renal replacement therapy for the total global dialysis population. But there are about 40% peritoneal patient drow out peritoneal dialysis due to peritoneal fibrosis and ultrafiltration failure. Peritoneal fibrosis (PF) is a serious pathophysiology of peritoneal dialysis (PD). The key of the success of the peritoneal dialysis is to reverse or delay the peritoneal fibrosis. Nitro-oleic acid (OA- NO2) is identified as endogenous potent ligands for proxisome proliferator-activated receptor subtype-γ (PPARγ) with few side effects. The previous study demonstrated that OA-NO2 showed multiple biological activities, such as anti-inflammation, anti-oxidative stress and anti-glomerular fibrosis. We got a clue from the preliminary experiment that OA-NO2 remarkably reduced high glucose induced the over-expression of the TGF-β and α-SMA in peritoneal mesothelial cells. In vitro study, the present study aim to test the benefical effects of the OA-NO2 on the fibrosis induced by high glucose, and to evaluate the role of the TGF-β/Smad pathway、oxidative stress、 inflammation and RAAS in the protective effects of the OA-NO2. Furthermore , in vivo study, the present study test the protective effects of OA-NO2 for peritoneal fibrosis and ultrafiltration capacity in classical peritoneal fibrosis animal model and study the detail signal pathway. The present study will provide strong evidence for the clinical use of OA-NO2 in future.

腹膜透析是尿毒症患者主要治疗方法之一，而约40% 的腹膜透析患者3 年后因腹膜超滤衰竭而终止腹膜透析，腹膜纤维化是腹膜超滤衰竭的主要原因，因此预防和延缓腹膜纤维化是保证长期腹膜透析患者透析成功的关键。硝基油酸是新型内源性PPARγ激动剂，在体内天然存在，我们前期在肾损伤动物模型中，证明硝基油酸通过抗炎、抗氧化应激等作用减轻肾损伤；并证明硝基油酸具有降糖和调节血脂等作用。我们预实验证实硝基油酸可明显抑制高糖诱导的腹膜间皮细胞转分化。因此，我们拟通过细胞实验证实硝基油酸对高糖诱导的腹膜间皮细胞纤维化的抑制作用，并通过检测氧化应激指标、炎症因子、TGF-β/smad通路、RASS系统的变化初步探讨其作用机制，且明确硝基油酸抑制纤维化作用是否依赖PPARγ介导；同时在腹膜纤维化动物模型中明确硝基油酸对腹膜功能保护和对腹膜纤维化的抑制作用及机制。本研究将为硝基油酸新的生物学活性提供更翔实的实验依据。