阻断PKCα改善高糖腹膜透析液诱导的腹膜纤维化的作用机制研究

High glucose dialysate induced peritoneal fibrosis is the most important cause of the failure of peritoneal dialysis . Lot’s of evidences show that Protein kinase C (PKC) can be activated by high glucose and than affect several classical signal pathway in the upstream , which directly activates TGF-β1-EMT signaling pathway , and increases the expression of VEGF level and a variety of inflammatory cytokines. It suggests the therapeutic potential by regulating PKC in the prevention or treatment of peritoneal fibrosis at early stage. The main activity of PKC is decided by its isoforms. The PKC family has at least 12 isoforms of different enzymatic properties and signaling functions. Until now there is no reports about which kind of PKC isoforms plays a decisive role in the high glucose -induced peritoneal fibrosis. Our previous experiments base on different PKC isoforms gene knockout mice suggest that PKCα subtypes may play an important role in peritoneal mesothelial cells EMT caused by high glucose. This study intends to clarify the mechanisem of blocking PKCα can improve high glucose induced peritoneal fibrosis and provide new drug for clinical treatment, using PKCα knockout mouse, PKCα inhibitor and clinical specimens by proteomics and flow cytometry technologies.

高糖透析液诱导的腹膜纤维化是导致腹膜透析失败的最重要原因。蛋白激酶C（PKC）是目前唯一有证据显示由高糖激活后直接调控多条导致腹膜纤维化经典通路的上游“总开关”，它激活TGF-β1—EMT信号通路，上调VEGF以及多种炎症因子表达水平，通过调节PKC活性就可在信号转导启动阶段防治腹膜纤维化。PKC不同亚型有各自独立的酶学特性并介导不同信号传导通路。目前国际上尚无报道究竟哪种PKC亚型在高糖腹透液诱导的腹膜纤维化中起决定性作用。本课题组前期实验通过对不同PKC亚型基因敲除小鼠的筛选，提示阻断PKCα可改善透析液高糖诱导的腹膜间皮细胞EMT。本研究拟应用PKCα基因敲除小鼠构建腹透模型，采集相关临床标本，应用药理学方法、蛋白质组学及流式技术，分别通过体外实验和在体实验阐明PKCα介导高糖腹透液诱导的腹膜纤维化的机制，为临床治疗腹膜透析并发症及其相关机制研究开辟了新的视野。

高糖透析液诱导的腹膜纤维化是导致腹膜透析失败的最重要原因。蛋白激酶C（PKC）是目前唯一有证据显示由高糖激活后直接调控多条导致腹膜纤维化经典通路的上游“总开关”，它激活TGF-β1—EMT信号通路，上调VEGF以及多种炎症因子表达水平，通过调节PKC活性就可在信号转导启动阶段防治腹膜纤维化。PKC不同亚型有各自独立的酶学特性并介导不同信号传导通路。本研究应用PKC亚型基因敲除小鼠构建腹透模型，采集相关临床标本，应用药理学方法、蛋白质组学及流式技术，分别通过体外实验和在体实验证实PKCα亚型是介导高糖腹透液诱导的腹膜纤维化的主要PKC亚型，并进一步阐明其机制，为临床治疗腹膜透析并发症及其相关机制研究开辟了新的视野。