1-Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway.

BACKGROUND AND PURPOSE In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal replacement therapies. Emerging evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of the metabolite 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 glomerular filtration rate 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. Upregulated mRNA expression of aryl hydrocarbon receptors (AhR) and its target genes, including CYP1A1, CYP1A2, and CYP1B1, was observed in both patients and rats with progressive CKD. Our study further showed upregulated mRNA expression of AhR and its three target genes and upregulated nuclear AhR protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Furthermore, treatment with AhR short hairpin RNA or flavonoids inhibited mRNA expression of AhR 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 AhR signalling pathway. Therefore, targeting AhR may be an alternative therapeutic strategy for CKD progression.