Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis -mediated mitophagy impairment
Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis -mediated mitophagy impairment
复制标题
硫酸吲哚酚通过 IRF1-DRP1 轴介导的线粒体自噬损伤诱导肠屏障损伤
DOI：
10.7150/thno.45455
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhao, Jinghong
中科院分区：
文献类型：
--
作者：
Huang, Yinghui;Zhou, Jie;Zhao, Jinghong
理论基础：肠-肾轴功能障碍形成恶性循环，最终成为慢性肾脏疾病(CKD)进展和相关并发症发生的催化剂。然而，CKD相关肠功能障碍的致病因素及其机制尚不清楚。方法：我们首先确定蛋白结合的尿毒症毒素吲哚硫酸盐(IS)可能与肠屏障损伤有关。用跨上皮电阻法、通透性测定和透射电子显微镜观察IS对肠上皮细胞、IS注射小鼠和CKD小鼠肠道屏障的损伤作用。通过体外和体内实验，探讨IS在肠屏障损伤中的作用及其机制。最后，用口服IS吸附剂AST-120处理的CKD小鼠和基因敲除小鼠验证其机制，并探索可能的干预措施。结果：IS显著抑制肠上皮细胞跨上皮电阻和紧密连接相关基因的表达。体外实验表明，IS可抑制动力蛋白相关蛋白1(Drp1)的表达和丝裂原通透性，而过表达Drp1则可减轻IS诱导的丝裂原抑制和肠上皮细胞损伤。此外，它通过上调干扰素调节因子1(IRF1)的表达来抑制DRp1，并且IRF1可以直接与DRp1的启动子区域结合。此外，在CKD患者的肠道组织中，观察到Drp1和自噬小体包裹的线粒体的表达减少。给予AST-120或基因敲除IRF1可减轻IS诱导的小鼠DRp1表达减少、丝裂原损伤和肠屏障损伤。结论：减少IS蓄积或靶向IRF1-Drp1轴可能是缓解CKD相关肠功能障碍的一种有前途的治疗策略。
Rationale: The dysfunctional gut-kidney axis forms a vicious circle, which eventually becomes a catalyst for the progression of chronic kidney disease (CKD) and occurrence of related complications. However, the pathogenic factors of CKD-associated intestinal dysfunction and its mechanism remain elusive.Methods: We first identified the protein-bound uremic toxin indoxyl sulfate (IS) as a possible contributor to intestinal barrier injury. Transepithelial electrical resistance, permeability assay and transmission electron microscopy were carried out to evaluate the damaging effect of IS on intestinal barrier in intestinal epithelial cells, IS-injected mice and CKD mice. In vitro and in vivo experiments were performed to investigate the role of IS in intestinal barrier injury and the underlying mechanism. Finally, CKD mice treated with AST-120 (an oral adsorbent for IS) and gene knockout mice were used to verify the mechanism and to explore possible interventions for IS-induced intestinal barrier injury.Results: Transepithelial electrical resistance and the expressions of tight junction-related genes were significantly suppressed by IS in intestinal epithelial cells. In vitro experiments demonstrated that IS inhibited the expression of dynamin-related protein 1 (DRP1) and mitophagic flux, whereas DRP1 overexpression attenuated IS-induced mitophagic inhibition and intestinal epithelial cell damage. Furthermore, IS suppressed DRP1 by upregulating the expression of interferon regulatory factor 1 (IRF1), and IRF1 could directly bind to the promoter region of DRP1. Additionally, the decreased expression of DRP1 and autophagosome-encapsulated mitochondria were observed in the intestinal tissues of CKD patients. Administration of AST-120 or genetic knockout of IRF1 attenuated IS-induced DRP1 reduction, mitophagic impairment and intestinal barrier injury in mice.Conclusions: These findings suggest that reducing IS accumulation or targeting the IRF1-DRP1 axis may be a promising therapeutic strategy for alleviating CKD-associated intestinal dysfunction.