Intrarenal 1-methoxypyrene,an aryl hydrocarbon receptor agonist,mediates progressive tubulointerstitial fibrosis in mice  

作　　者：Gang Cao Hua Miao Yan-ni Wang Dan-qian Chen Xia-qing Wu Lin Chen Yan Guo Liang Zou Nosratola D.Vaziri Ping Li Ying-yong Zhao 

机构地区：[1]School of Pharmacy,Zhejiang Chinese Medical University,No.548 Binwen Road,Hangzhou 310053,China [2]Faculty of Life Science&Medicine,Northwest University,No.229 Taibai North Road,Xi’an 710069,China [3]Beijing Key Lab for Immune-Mediated Inflammatory Diseases,Institute of Clinical Medical Science,Department of Nephrology,China-Japan Friendship Hospital,No.2 Yinghua East Road,Beijing 100029,China [4]Department of Internal Medicine,University of New Mexico,1700 Lomas Blvd NE,Albuquerque,NM 87131,USA [5]School of Food and Bioengineering,Chengdu University,No.2025 Chengluo Avenue,Chengdu 610106,China [6]Division of Nephrology and Hypertension,School of Medicine,University of California Irvine,1001 Health Sciences Rd,Irvine,CA 92897,USA

出　　处：《Acta Pharmacologica Sinica》2022年第11期2929-2945,共17页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(Nos.82074002,81922073,81872985);the National Key Research and Development Project of China(No.2019YFC1709405).

摘　　要：Recent studies have shown that endogenous metabolites act via aryl hydrocarbon receptor(AhR)signalling pathway in tubulointerstitial fibrosis(TIF)pathogenesis.However,the mechanisms underlying endogenous metabolite-mediated AhR activation are poorly characterised.In this study,we conducted untargeted metabolomics analysis to identify the significantly altered intrarenal metabolites in a mouse model of unilateral ureteral obstruction(UUO).We found that the levels of the metabolite 1-methoxypyrene(MP)and the mRNA expression of AhR and its target genes CYP1A1,CYP1A2,CYP1B1 and COX-2 were progressively increased in the obstructed kidney at Weeks 1,2 and 3.Furthermore,these changes were positively correlated with progressive TIF in UUO mice.In NRK-52E,RAW 264.7 and NRK-49F cells,MP dose-dependently upregulated the mRNA expression of AhR and its four target genes and the protein expression of nuclear AhR,accompanied by the upregulated protein expression of collagen I,α-SMA and fibronectin,as well as downregulated E-cadherin expression.Consistently,oral administration of MP in mice progressively enhanced AhR activity and upregulated profibrotic protein expression in the kidneys;these effects were partially inhibited by AhR knockdown in MP-treated mice and cell lines.In addition,we screened and identified erythro-guaiacylglycerol-β-ferulic acid ether(GFA),which was isolated from Semen plantaginis,as a new AhR antagonist.GFA significantly attenuated TIF in MP-treated NRK-52E cells and mice by partially antagonising AhR activity.Our results suggest that MP activates AhR signalling,thus mediating TIF through epithelial-mesenchymal transition and macrophage-myofibroblast transition.MP is a crucial metabolite that contributes to TIF via AhR signalling pathway.

关 键 词：tubulointerstitial fibrosis aryl hydrocarbon receptor epithelial-mesenchymal transition macrophage-myofibroblast transition metabolomics Semen plantaginis 

分 类 号：R965[医药卫生—药理学]