In:
British Journal of Pharmacology, Wiley, Vol. 179, No. 1 ( 2022-01), p. 103-124
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2029728-2
SSG:
15,3
