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

Gang Cao1, Hua Miao2, Yan-ni Wang2, Dan-qian Chen3, Xia-qing Wu2, Lin Chen2, Yan Guo4, Liang Zou5, Nosratola D. Vaziri6, Ping Li3, Ying-yong Zhao1,2
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
Correspondence to: Gang Cao:, Ping Li:, Ying-yong Zhao:,
DOI: 10.1038/s41401-022-00914-6
Received: 14 February 2022
Accepted: 17 April 2022
Advance online: 16 May 2022


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.

Keywords: tubulointerstitial fibrosis; aryl hydrocarbon receptor; epithelial-mesenchymal transition; macrophage-myofibroblast transition; metabolomics; Semen plantaginis

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