XBP1s在腹膜间皮细胞中的表达对于炎症诱导的腹膜纤维化至关重要。,Scientific Reports

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XBP1s在腹膜间皮细胞中的表达对于炎症诱导的腹膜纤维化至关重要。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-13 , DOI: 10.1038/s41598-019-55557-1
An Liu ₁ , Qiong Song ₂ , Yong Zheng ₃ , Guoshuang Xu ₃ , Chen Huang ₃ , Shiren Sun ₃ , Lijie He ₃ , Lijuan Zhao ₃ , Meilan Zhou ₃

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腹膜内炎症是长期腹膜透析（PD）患者腹膜纤维化的最重要决定因素。剪接的x-box结合蛋白1（XBP1s）是未折叠蛋白应答（UPR）信号的主要近端效应子，在炎症中起着不可或缺的作用。我们的研究表明，炎症因子白介素-1β（IL-1β）剂量和时间依赖性地诱导XBP1s上调和白介素6（IL-6）分泌，以及纤维化标记纤连蛋白的表达。但是，IRE1核酸内切酶抑制剂STF083010阻止了这些作用，因为它在时间上减少了人腹膜间皮细胞中IL-1β诱导的Xbp1 mRNA剪接，XBP1s蛋白表达，炎性因子IL-6分泌以及纤维化标记纤连蛋白的表达。（HPMC）。XMC1s在HPMCs中的过表达和敲除对纤连蛋白的表达具有相似的影响。在腹膜炎症的大鼠模型中，STF083010显着减弱了洗必太二葡萄糖酸诱导的腹膜内XBP1s和α-平滑肌肌动蛋白的表达以及纤维化组织的增殖。我们的结果表明，XBP1s是一种强大的致病因子，可在腹膜透析中介导炎症诱导的腹膜纤维化。

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Expression of XBP1s in peritoneal mesothelial cells is critical for inflammation-induced peritoneal fibrosis.

Intraperitoneal inflammation is the most important determinant of peritoneal fibrosis in patients with long-term peritoneal dialysis (PD). Spliced x-box binding protein-1 (XBP1s), a major proximal effector of unfolded protein response (UPR) signaling, plays an indispensable role in inflammation. Our study demonstrated that the inflammatory factor interleukin-1β (IL-1β) dose- and time-dependently induced XBP1s upregulation and interleukin-6 (IL-6) secretion, as well as the expression of the fibrotic marker fibronectin. However, these effects were prevented by the IRE1 endonuclease inhibitor STF083010 since it time-dependently reduced IL-1β-induced Xbp1 mRNA splicing, XBP1s protein expression, inflammatory factor IL-6 secretion and the expression of the fibrotic marker fibronectin in human peritoneal mesothelial cells (HPMCs). The overexpression and knockdown of XBP1s in HPMCs had a similar effect on fibronectin expression. In a rat model of peritoneal inflammation, STF083010 significantly attenuated chlorhexidine digluconate-induced XBP1s and α-smooth muscle actin expression, as well as fibrotic tissue proliferation, in the peritoneum. Our results suggest that XBP1s is a strong pathogenic factor that mediates inflammation-induced peritoneal fibrosis in peritoneal dialysis.

更新日期：2019-12-13

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