Activation of NRF2 Signaling in HEK293 Cells by a First-in-Class Direct KEAP1-NRF2 Inhibitor

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Xia Wen1, Gabriell Thorne2, Longqin Hu3

  • 1Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, NJ, 08854, USA.

Journal of Biochemical and Molecular Toxicology
|February 17, 2015
PubMed

Insights

LH601A directly inhibits the KEAP1-NRF2 interaction, activating the antioxidant nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. This compound shows potential for defending against kidney injury and diseases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • The antioxidant transcription factor NRF2 is typically degraded by KEAP1.
  • Upon cellular injury, NRF2 dissociates from KEAP1 to activate protective genes.
  • KEAP1-NRF2 interaction is crucial for cellular defense mechanisms.

Purpose of the Study:

  • To investigate if LH601A activates NRF2 signaling in human kidney cells.
  • To evaluate LH601A as a direct inhibitor of the KEAP1-NRF2 protein-protein interaction.
  • To explore the therapeutic potential of LH601A in kidney injury.

Main Methods:

  • Treatment of human embryonic kidney 293 (HEK293) cells with LH601A or sulforaphane (SFN).
  • Incubation periods of 6 or 16 hours.
  • Analysis of NRF2 target gene mRNA and protein expression.

Main Results:

  • LH601A and SFN upregulated mRNA levels of NRF2 targets: HO-1, TRX1, and NQO1.
  • Both compounds increased the protein expression of HO-1 and TRX1.
  • LH601A effectively activated NRF2 signaling in kidney cells.

Conclusions:

  • LH601A is a first-in-class direct inhibitor of the KEAP1-NRF2 interaction.
  • LH601A activates NRF2 signaling, leading to the expression of protective genes.
  • LH601A may serve as a therapeutic agent against kidney injury and diseases.
Keywords:
HO-1KEAP1KidneyNRF2Nephrotoxicity

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