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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI

Xiaowen Yu1,2,3, Man Xu1,2,3, Xia Meng1,2,3

  • 1Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.

Science Translational Medicine
|May 15, 2020
PubMed

Insights

Activating pregnane X receptor (PXR) protects against acute kidney injury (AKI) by targeting AKR1B7 to improve mitochondrial function. Disabling this pathway worsens kidney injury, suggesting therapeutic potential.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Acute kidney injury (AKI) is a significant global health issue lacking effective treatments.
  • The role of the nuclear pregnane X receptor (PXR) in kidney injury is not well understood.
  • PXR is implicated in various diseases, including metabolic disorders and liver injury.

Purpose of the Study:

  • To investigate the role of PXR in the development and progression of AKI.
  • To elucidate the underlying molecular mechanisms of PXR's function in kidney injury.
  • To explore PXR as a potential therapeutic target for AKI.

Main Methods:

  • Analysis of PXR expression in human and animal AKI models.
  • In vivo studies involving PXR silencing and activation in rat models of AKI (cisplatin and ischemia/reperfusion).
  • Luciferase reporter assays, genomic manipulation, and proteomics to identify PXR targets.
  • Assessment of mitochondrial function and renal dysfunction.

Main Results:

  • PXR expression was significantly downregulated in kidneys affected by AKI.
  • PXR silencing exacerbated cisplatin-induced AKI and mitochondrial damage.
  • PXR activation demonstrated a protective effect against AKI.
  • PXR was identified to target Aldo-keto reductase family 1, member B7 (AKR1B7), enhancing mitochondrial function.
  • Restoration of the PXR/AKR1B7/mitochondrial metabolism axis ameliorated kidney injury in both cisplatin and ischemia/reperfusion models.

Conclusions:

  • The PXR/AKR1B7/mitochondrial metabolism axis plays a crucial role in protecting against AKI.
  • Downregulation of this axis contributes to AKI pathogenesis.
  • Re-establishing the PXR/AKR1B7 pathway offers a promising therapeutic strategy for AKI.

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