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1‐Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway
- Source :
- British Journal of Pharmacology. 179:103-124
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- BACKGROUND AND PURPOSE In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.
- Subjects :
- Metabolite
CYP1B1
Renal function
Pharmacology
urologic and male genital diseases
Small hairpin RNA
Mice
chemistry.chemical_compound
Cytochrome P-450 CYP1A1
medicine
Renal fibrosis
Animals
Humans
Renal Insufficiency, Chronic
Kidney
Pyrenes
biology
medicine.disease
Aryl hydrocarbon receptor
Fibrosis
Rats
medicine.anatomical_structure
Receptors, Aryl Hydrocarbon
chemistry
biology.protein
Kidney disease
Subjects
Details
- ISSN :
- 14765381 and 00071188
- Volume :
- 179
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....bce0864f9111d35c877d59d382b1d2fa