Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

Peritoneal fibrosis (PF) ultimately causes ultrafiltration failure and peritoneal dialysis (PD) termination, but there are few effective therapies for it. Core fucosylation, which is catalyzed by α1,6-fucosyltransferase (Fut8) in mammals, may play a crucial role in PF development. This study aims to assess the effects of inhibiting core fucosylation of epidermal growth factor (EGF) receptor on PF rats.
PF rats (established by 4.25% glucose dialysate) were treated with either an adenovirus-Fut8 short hairpin RNA (Fut8shRNA) or adenovirus-control. Masson’s staining and net ultrafiltration were performed at week six. Fut8 level and core fucosylation of EGF receptor and collagen I in the peritoneal membrane were assessed, and EGF signaling was detected, including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB) and their phosphorylation. Monocyte chemoattractant protein-1 (MCP-1) in peritoneal effluent was examined.
Fut8 was upregulated in PF rats but decreased after Fut8shRNA treatment. EGF and EGF receptor expression was upregulated in PF rats, while core fucosylation of EGF receptor decreased after Fut8shRNA treatment. Masson’s staining results showed an increase in peritoneal thickness in PF rats but a decrease after Fut8shRNA treatment. Fut8shRNA treatment increased net ultrafiltration, reduced the expression of collagen I and MCP-1 compared to PF rats. Fut8shRNA treatment suppressed phosphorylation of STAT3 and NF-κB in the peritoneal membrane of PF rats.
Fut8shRNA treatment ameliorated the fibrotic changes in PF rats. A potential mechanism may be that Fut8shRNA treatment inactivated EGF signaling pathway by suppressing the phosphorylation of STAT3 and NF-κB.

腹膜纤维化（Peritoneal fibrosis, PF）最终会导致超滤失败及腹膜透析（Peritoneal dialysis, PD）终止，但目前针对该病的有效治疗手段十分匮乏。核心岩藻糖基化（core fucosylation）由哺乳动物中的α1,6-岩藻糖基转移酶（α1,6-fucosyltransferase, Fut8）催化，可能在PF的发生发展中发挥关键作用。本研究旨在探究抑制表皮生长因子（epidermal growth factor, EGF）受体核心岩藻糖基化对PF大鼠模型的干预效果。

通过4.25%葡萄糖透析液诱导构建的PF大鼠模型被分为两组，分别经腺病毒介导的Fut8短发夹RNA（adenovirus-Fut8 short hairpin RNA, Fut8shRNA）及腺病毒空载处理。于造模后第6周进行Masson染色及净超滤量检测；检测腹膜组织中Fut8的表达水平、EGF受体及Ⅰ型胶原蛋白的核心岩藻糖基化水平，并检测EGF信号通路相关分子，包括信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）、核因子κB（nuclear factor kappa B, NF-κB）及其磷酸化水平；同时检测腹膜透析流出液中的单核细胞趋化蛋白-1（monocyte chemoattractant protein-1, MCP-1）含量。

PF模型大鼠体内Fut8表达上调，而经Fut8shRNA干预后其表达水平显著降低。PF模型大鼠中EGF及EGF受体表达上调，经Fut8shRNA干预后，EGF受体的核心岩藻糖基化水平显著降低。Masson染色结果显示，PF模型大鼠腹膜厚度增加，经Fut8shRNA干预后腹膜厚度显著降低。与PF模型组大鼠相比，Fut8shRNA干预组的净超滤量升高，Ⅰ型胶原蛋白及MCP-1的表达水平显著降低；同时Fut8shRNA干预可抑制PF大鼠腹膜组织中STAT3及NF-κB的磷酸化水平。

Fut8shRNA干预可改善PF模型大鼠的纤维化病变。其潜在作用机制可能为：Fut8shRNA通过抑制STAT3及NF-κB的磷酸化，从而阻断EGF信号通路的激活。