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miR-125b transcriptionally increased by Nrf2 inhibits AhR repressor, which protects kidney from cisplatin-induced

M S Joo1, C G Lee, J H Koo

  • 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.

Cell Death & Disease
|November 2, 2013
PubMed

Insights

Nuclear factor erythroid-2-related factor 2 (Nrf2) activates miR-125b, which protects the kidney from injury by inhibiting the aryl hydrocarbon receptor repressor (AhRR). This pathway enhances cellular defense mechanisms against toxins.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Toxicology

Background:

  • MicroRNAs (miRNAs) are key regulators of cellular defense mechanisms.
  • Nuclear factor erythroid-2-related factor 2 (Nrf2) enhances antioxidant capacity but its control over miRNAs is uncharacterized.
  • Understanding Nrf2-regulated miRNAs is crucial for cellular protection strategies.

Purpose of the Study:

  • To identify and characterize miRNAs transcriptionally regulated by Nrf2.
  • To investigate the role of a novel Nrf2-regulated miRNA in kidney protection.
  • To elucidate the molecular mechanism of miR-125b in regulating aryl hydrocarbon receptor (AhR) activity and cellular survival.

Main Methods:

  • Bioinformatic analysis to identify candidate miRNAs.
  • In vivo studies using mice treated with oltipraz and cisplatin.
  • Nrf2 overexpression and knockout models.
  • Functional assays including miR-125b mimic and small interfering RNA (siRNA) for AhRR.
  • Analysis of gene and protein expression levels (e.g., AhRR, mdm2, p53).

Main Results:

  • miR-125b was identified as a direct Nrf2 target gene, upregulated by oltipraz and cisplatin.
  • Nrf2 overexpression increased miR-125b levels; Nrf2 knockout exacerbated cisplatin-induced kidney injury.
  • miR-125b was found to inhibit AhRR, leading to AhR activation and mdm2 induction.
  • miR-125b and oltipraz treatment diminished p53 activation by cisplatin, protecting the kidney.
  • Experiments confirmed miR-125b's role in AhRR regulation and kidney protection.

Conclusions:

  • miR-125b is transcriptionally activated by Nrf2.
  • miR-125b acts as a crucial inhibitor of AhRR, modulating AhR activity.
  • This Nrf2-miR-125b-AhRR axis plays a significant role in protecting the kidney from acute injury.

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