2. Academic Validation
  3. 1-Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway

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

  • Br J Pharmacol. 2022 Jan;179(1):103-124. doi: 10.1111/bph.15705.
Hua Miao 1,  Xia-Qing Wu 1,  Yan-Ni Wang 1,  Dan-Qian Chen 1,  Lin Chen 1,  Nosratola D Vaziri 2,  Shougang Zhuang 3 4,  Yan Guo 5,  Wei Su 6,  Shi-Xing Ma 6,  Huan-Qiao Zhang 6,  You-Quan Shang 6,  Xiao-Yong Yu 7,  Yan-Long Zhao 7,  Jia-Rong Mao 7,  Ming Gao 8,  Jin-Hua Zhang 8,  Jin Zhao 8,  Yuan Zhang 8,  Li Zhang 8,  Ying-Yong Zhao 1,  Gang Cao 9
Affiliations

Affiliations

  • 1 Faculty of Life Science and Medicine, Northwest University, Xi'an, China.
  • 2 Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, California, USA.
  • 3 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA.
  • 5 Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
  • 6 Department of Nephrology, Baoji Central Hospital, Baoji, China.
  • 7 Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi'an, China.
  • 8 Department of Nephrology, Xi'an No. 4 Hospital, Xi'an, China.
  • 9 School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China.
PMID: 34625952 DOI: 10.1111/bph.15705
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.

Keywords

1-hydroxypyrene; aryl hydrocarbon receptor; chronic kidney disease; flavonoid; glomerular filtration rate; metabolomics.

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