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Ochratoxin A induces cytoprotective autophagy via blocking AKT/mTOR signaling pathway in PK-15 cells

Gang Qian1, Dandan Liu2, Lili Hou2

  • 1College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China; Department of Animal Science and Technology, Jinling Institution of Technology, Nanjing, 210095, Jiangsu Province, China.

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
|October 6, 2018
PubMed

Insights

Ochratoxin A (OTA) triggers protective autophagy, a cellular process, to counteract its own toxicity. Inhibiting autophagy enhances OTA

Area of Science:

  • Toxicology
  • Cellular Biology
  • Molecular Biology

Background:

  • Ochratoxin A (OTA) is a mycotoxin known for its nephrotoxic effects in humans and animals.
  • Autophagy, a cellular degradation process, is crucial for maintaining homeostasis under stress.
  • The specific role of autophagy in OTA-induced kidney toxicity remained unclear.

Purpose of the Study:

  • To investigate the role of autophagy in Ochratoxin A (OTA)-induced cytotoxicity in PK-15 cells.
  • To elucidate the molecular mechanisms underlying OTA-induced autophagy and its protective effects.

Main Methods:

  • PK-15 cells were treated with varying concentrations of OTA (2.0-8.0 μM).
  • Apoptosis was assessed via Annexin V/PI staining, caspase-3/PARP cleavage, and nuclear morphology.
  • Autophagy markers (LC3-II, ATG5, Beclin-1), GFP-LC3 puncta, and vesicle formation were analyzed.
  • Western blotting was used to evaluate AKT/mTOR signaling pathway activity.
  • Autophagy inhibitors (3-MA, chloroquine) and gene knockdown (ATG5, Beclin-1) were employed.

Main Results:

  • OTA treatment increased PK-15 cell cytotoxicity by inducing apoptosis.
  • OTA significantly triggered autophagy, evidenced by increased LC3-II, ATG5, Beclin-1, GFP-LC3 dots, and vesicle accumulation.
  • OTA decreased phosphorylation of AKT and mTOR, suggesting pathway inactivation.
  • Insulin treatment partially inhibited OTA-induced autophagy.
  • Inhibition of autophagy (pharmacological or genetic) exacerbated OTA-induced cytotoxicity.

Conclusions:

  • Ochratoxin A (OTA) induces a cytoprotective autophagic response against its own toxicity.
  • The inactivation of the AKT/mTOR signaling pathway is critical for OTA-induced autophagy.
  • Targeting autophagy modulation may offer therapeutic strategies against OTA nephrotoxicity.
Keywords:
AKT/mTORApoptosisAutophagyNephrotoxicityOchratoxin A

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