Ochratoxin A induces nephrotoxicity in vitro and in vivo via pyroptosis

Area of Science:

• Toxicology
• Cell Biology
• Immunology

Background:

• Ochratoxin A (OTA) is a mycotoxin found in food and feed, known to cause kidney damage.
• The precise mechanisms underlying OTA-induced nephrotoxicity, particularly the role of pyroptosis, require further investigation.

Purpose of the Study:

• To elucidate the nephrotoxic effects of continuous Ochratoxin A administration.
• To investigate the involvement of pyroptosis and the NLRP3 inflammasome in OTA-induced kidney injury.

Main Methods:

• Male C57BL/6 mice were injected with OTA (1.0 and 2.0 mg/kg) every other day for 14 days.
• Madin-Darby canine kidney (MDCK) cells were exposed to varying concentrations of OTA (0-4.0 μg/ml) for 24 hours.
• Inhibition of NLRP3 inflammasome and caspase-1 was achieved using MCC950, siRNA, and genetic knockdown.

Main Results:

• OTA administration (2.0 mg/kg) significantly increased renal histological injury, fibrosis markers (α-SMA, Vimentin, TGF-β), and activated the NLRP3 inflammasome, leading to pyroptosis in mice.
• In vitro, OTA dose-dependently reduced MDCK cell viability and upregulated fibrosis genes.
• OTA induced NLRP3 inflammasome activation and caspase-1-dependent pyroptosis in MDCK cells, increasing pro-inflammatory cytokines (IL-6, TNF-α) and pyroptosis markers (GSDMD, IL-1β, IL-18).
• Inhibition of NLRP3 or caspase-1 ameliorated OTA-induced renal fibrosis and pyroptosis.

Conclusions:

• Ochratoxin A triggers nephrotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis.
• Targeting the NLRP3 inflammasome and pyroptosis pathways presents a potential therapeutic strategy against OTA-induced kidney damage.