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
  • 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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