Journal
ACTA PHARMACOLOGICA SINICA
Volume 43, Issue 11, Pages 2929-2945Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-022-00914-6
Keywords
tubulointerstitial fibrosis; aryl hydrocarbon receptor; epithelial-mesenchymal transition; macrophage-myofibroblast transition; metabolomics; Semen plantaginis
Funding
- National Natural Science Foundation of China [82074002, 81922073, 81872985]
- National Key Research and Development Project of China [2019YFC1709405]
Ask authors/readers for more resources
This study found that the metabolite 1-methoxypyrene (MP) activates the aryl hydrocarbon receptor (AhR) signaling pathway, leading to tubulointerstitial fibrosis (TIF). MP promotes the epithelial-mesenchymal transition and macrophage-myofibroblast transition, which are important for the development of TIF.
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, alpha-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-beta-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available