Common molecular mechanism of aristolochic acid I inducing hepatorenal toxicity

Jing WANG; Gerui ZHU; Kai HUANG; Yuan PENG; Chenghai LIU; Yanyan TAO

doi:10.16305/j.1007-1334.2022.2103059

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Common molecular mechanism of aristolochic acid I inducing hepatorenal toxicity

更新时间：2022-07-13

- Common molecular mechanism of aristolochic acid I inducing hepatorenal toxicity
- Shanghai Journal of Traditional Chinese Medicine Vol. 56, Issue 5, Pages: 60-67(2022)
- 作者机构：
  
  1.上海中医药大学附属曙光医院肝二科（上海 201203）
  2.上海中医药大学肝病研究所（上海 201203）
  3.上海市中医临床重点实验室（上海 201203）
  4.肝肾疾病病证教育部重点实验室（上海中医药大学）（上海 201203）
- 作者简介：
- 基金信息：
- DOI：10.16305/j.1007-1334.2022.2103059
  CLC：
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王静,朱哿瑞,黄恺等.马兜铃酸Ⅰ致肝、肾毒性的共性分子机制研究[J].上海中医药杂志,2022,56(05):60-67.

WANG Jing,ZHU Gerui,HUANG Kai,et al.Common molecular mechanism of aristolochic acid I inducing hepatorenal toxicity[J].Shanghai Journal of Traditional Chinese Medicine,2022,56(05):60-67.
王静,朱哿瑞,黄恺等.马兜铃酸Ⅰ致肝、肾毒性的共性分子机制研究[J].上海中医药杂志,2022,56(05):60-67. DOI： 10.16305/j.1007-1334.2022.2103059.

WANG Jing,ZHU Gerui,HUANG Kai,et al.Common molecular mechanism of aristolochic acid I inducing hepatorenal toxicity[J].Shanghai Journal of Traditional Chinese Medicine,2022,56(05):60-67. DOI： 10.16305/j.1007-1334.2022.2103059.

摘要

目的,2,基于转录组学分析马兜铃酸Ⅰ（AAⅠ）致小鼠肝、肾损伤的共性分子机制。,方法,2,雄性C57BL/6小鼠随机分为正常组（,n,=6）和模型组（,n,=9），模型组小鼠AAⅠ以20 mg/kg剂量腹腔注射，每天1次，连续5 d后处死。检测两组小鼠血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、肌酐（SCr）、尿素氮（BUN）含量和肝、肾组织病理特点；取正常组与模型组各3个肝、肾组织，提取RNA进行高通量转录组测序，将基因表达量差异倍数（FC）≥2.0且,P,<,0.01定义为差异基因，分别筛选正常组肝、肾组织与模型组肝、肾组织的差异基因，再取肝、肾差异基因的交集，应用基因本体（GO）、京都基因与基因组百科全书（KEGG）数据库进行富集功能分析；通过蛋白互作网络分析找出关联基因最多的差异基因进行qRT-PCR验证。,结果,2,与正常组比较，模型组血清ALT、AST活性及SCr、BUN含量明显升高，肝组织可见肝小叶结构紊乱、灶状坏死和轻度汇管区炎症，肾组织可观察到肾小球水肿、肾小球固缩以及肾小管上皮细胞坏死、脱落。转录组测序提示，肝、肾的共同差异基因为298个。对肝、肾共同差异基因进行GO和KEGG富集分析，发现小分子分解代谢、有机酸分解代谢、羧酸分解代谢、氧化还原酶活性、抗氧化活性、谷胱甘肽过氧化物酶活性等相关的GO分类呈显著富集；碳代谢、胰岛素抵抗、补体和凝血级联、NF-κb、JAK-STAT及PPAR信号通路等在KEGG通路中显著富集；蛋白互作网络分析及qRT-PCR验证提示，,Stat3、Cdh1、Myc、Ugt2b38、Egr1,等基因明显差异表达，与转录组结果一致。,结论,2,转录组学揭示AAⅠ致肝、肾毒性的共性机制主要涉及补体和凝血级联、氧化还原过程、NF-κb、JAK-STAT信号通路等环节。后续需针对,Stat3、Cdh1、Myc,等基因进一步深入探讨AAⅠ的肝肾毒性机制。

Abstract

Objactive, To explore the common mechanism of aristolochic acid I （AAⅠ） inducing liver and kidney injury in mice based on transcriptomics.,Methods,2,Male C57BL/6 mice were randomly divided into the normal group （,n,=6） and the model group （,n,=9）. The mice in the model group AAⅠ was injected intraperitoneally with a dose of 20 mg/kg once a day for 5 d and then executed. The contents of SCr， BUN， ALT and AST in serum were detected， and histological and pathological characteristics of liver and kidney were analyzed in two groups of mice. RNA was extracted from three liver and kidney tissues of the normal group and the model group respectively， and sequenced by high-throughput transcriptome. Differential genes were defined as differentially expressed genes （Fold Change） ≥2.0 and ,P,<,0.01. The differential genes in normal liver， kidney and model liver and kidney were screened respectively， and the intersection of differential genes in the liver and kidney was analyzed by gene ontology（GO）and Kyoto encyclopedia of genes and genomes（KEGG）database. The differential genes with the most related genes were identified by protein interaction network analysis and verified by qRT-PCR.,Results,2,Compared with the normal group， the activities of ALT and AST in serum and the contents of SCr and BUN in the model group were significantly increased. The structural disorders of hepatic lobule， focal necrosis and mild inflammation in the portal area were observed in the liver tissue， and glomerular edema， glomerular pyknosis and renal tubular epithelial cell necrosis and exfoliation were observed in the renal tissue. Transcriptome sequencing showed that there were 298 common differential genes in the liver and kidney. GO and KEGG analysis of common differential genes in the liver and kidney showed that GO classification related to small molecular catabolism， organic acid catabolism， carboxylic acid catabolism， oxidoreductase activity， antioxidant activity and glutathione peroxidase activity was significantly enriched， and carbon metabolism， insulin resistance， complement and coagulation cascade， NF-κb， JAK-STAT and PPAR signaling pathways were significantly enriched in KEGG pathway. Protein interaction network analysis and qRT-PCR verification showed that there were significant differences in the expressions of ,Stat3， Cdh1， Myc， Ugt2b38, and ,Egr1,， which were consistent with the results of transcriptome.,Conclusions,2,Transcriptome reveals that the common mechanism of hepatorenal toxicity induced by AAⅠ is mainly related to complement and coagulation cascade， redox process， NF-κb， JAK-STAT signal pathway and so on. The hepatorenal toxicity mechanism of AAⅠ should be further explored based on ,Stat3， Cdh1， Myc, and other genes.

关键词

马兜铃酸I转录组学肝肾毒性小鼠中药研究

Keywords

aristolochic acidtranscriptomicshepatorenal toxicitymicetraditional Chinese herbal medicine research

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