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

Hua Miao1, Xia-Qing Wu1, Yan-Ni Wang1

  • 1Faculty of Life Science and Medicine, Northwest University, Xi'an, China.

British Journal of Pharmacology
|October 9, 2021
PubMed
Abstract

Insights

The metabolite 1-hydroxypyrene drives kidney fibrosis by activating the aryl hydrocarbon receptor pathway. Targeting this pathway offers a potential therapeutic strategy for chronic kidney disease (CKD) progression.

Area of Science:

  • Nephrology
  • Metabolomics
  • Molecular Biology

Background:

  • Chronic kidney disease (CKD) is linked to metabolite disorders, but the underlying molecular pathways are not fully understood.
  • 1-hydroxypyrene is identified as a metabolite potentially involved in CKD pathogenesis.

Purpose of the Study:

  • To investigate the role of 1-hydroxypyrene in mediating renal fibrosis in chronic kidney disease (CKD).
  • To elucidate the molecular mechanisms by which 1-hydroxypyrene affects kidney function and fibrosis.

Main Methods:

  • Metabolomic analysis of 5406 urine and serum samples from CKD patients (Stage 1-5).
  • Validation in longitudinal, drug intervention, and animal (5/6 nephrectomized and adenine-induced rats) cohorts.
  • Analysis of aryl hydrocarbon receptor (AhR) and its target gene expression in patient and animal samples, and cell/tissue cultures.

Main Results:

  • 1-hydroxypyrene levels correlated with estimated GFR and renal function decline in CKD patients and rat models.
  • Increased expression of AhR and its target genes (CYP1A1, CYP1A2, CYP1B1) observed in progressive CKD.
  • 1-hydroxypyrene treatment upregulated AhR signaling, leading to extracellular matrix accumulation and fibrosis; inhibition of AhR pathway ameliorated these effects.

Conclusions:

  • 1-hydroxypyrene mediates renal fibrosis via aryl hydrocarbon receptor (AhR) pathway activation.
  • Targeting the AhR pathway presents a potential therapeutic strategy for managing CKD progression.
Keywords:
1-hydroxypyrenearyl hydrocarbon receptorchronic kidney diseaseflavonoidglomerular filtration ratemetabolomics

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