Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats
Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats
复制标题
抑制核心岩藻糖基化可减轻葡萄糖诱导的大鼠腹膜纤维化
DOI：
10.1016/j.kint.2017.12.023
复制
发表时间：
2018-06-01
影响因子：
19.6
通讯作者：
Wu, Taihua
中科院分区：
文献类型：
--
作者：
Li, Longkai;Shen, Nan;Wu, Taihua
超滤失败是长期腹膜透析的主要并发症，导致透析失败。持续暴露于高糖透析液导致的腹膜纤维化是超滤失败的主要原因，目前尚无有效的治疗方法。转化生长因子-β1(转化生长因子-β1)和血小板衍生生长因子(PDGF)等信号通路的过度激活参与了腹膜纤维化的发展。因此，同时阻断多条信号通路可能成为治疗腹膜纤维化的一种新方法。先前，我们发现核心岩藻糖化是转化生长因子-β1受体的一个重要的翻译后修饰，在肾间质纤维化中可以调节转化生长因子-β1信号的激活。然而，目前尚不清楚核心岩藻糖化是否影响腹膜纤维化的进展。在此，我们发现在高糖透析液诱导的腹膜纤维化大鼠的腹膜中，岩藻糖基化核心丰富。阻断核心岩藻糖化显著减轻通过同时失活转化生长因子-β1和血小板衍生生长因子信号通路而实现的大鼠腹膜纤维化。接下来比较了阻断核心岩藻糖基化和选择性PDGF受体抑制剂伊马替尼对腹膜纤维化的保护作用，发现阻断核心岩藻糖基化和伊马替尼对腹膜纤维化的抑制作用比单用伊马替尼更强，提示阻断多条信号通路的激活对腹膜纤维化的发展可能具有更好的抑制作用。因此，核心岩藻糖基化通过调节多个信号通路的激活，在腹膜纤维化的发生发展中起着至关重要的作用。这可能是治疗腹膜纤维化药物开发的潜在新靶点。
Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-beta 1 (TGF-(beta 1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-beta 1 receptors, can regulate the activation of TGF-beta 1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-beta 1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis.