2. Academic Validation
  3. Farnesoid X Receptor Plays a Key Role in Ochratoxin A-Induced Nephrotoxicity by Targeting Ferroptosis In Vivo and In Vitro

Farnesoid X Receptor Plays a Key Role in Ochratoxin A-Induced Nephrotoxicity by Targeting Ferroptosis In Vivo and In Vitro

  • J Agric Food Chem. 2023 Sep 26. doi: 10.1021/acs.jafc.3c04560.
Jiangyu Tang 1 2 3,  Junya Zeng 1 2 3,  Li Chen 1 2 3,  Mengmeng Wang 1 2 3,  Suibin He 1 4,  Azhar Muhmood 1 2 3,  Xingxiang Chen 1 2 3,  Kehe Huang 1 2 3,  Fang Gan 1 2 3
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.
  • 2 Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.
  • 3 MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.
  • 4 Animal Husbandry and Aquatic Products Technology Promotion Center of Pudong New Area, Shanghai 201299, China.
PMID: 37750412 DOI: 10.1021/acs.jafc.3c04560
Abstract

The mycotoxin ochratoxin A (OTA) causes nephrotoxicity, hepatotoxicity, and immunotoxicity in Animals and humans. The farnesoid X receptor (FXR) is a member of the NR family and is highly expressed in the kidney, which has an antilipid production function. Ferroptosis is an iron-dependent form of regulated cell death involved in several pathophysiological cell death and kidney injury. The present study aims to evaluate the role of FXR and Ferroptosis in OTA-induced nephrotoxicity in mice and HK-2 cells. Results showed that OTA induced nephrotoxicity as demonstrated by inducing the histopathological lesions and neutrophil infiltration of the kidney, increasing serum BUN, CRE, and UA levels, increasing Ntn-1, Kim-1, and pro-inflammatory cytokine expression, and decreasing IL-10 expression and the cell viability of HK-2 cells. OTA treatment also induced FXR deficiency, ROS release, MDA level increase, GSH content decrease, and 4-HNE production in the kidney and HK-2 cells. OTA treatment induced Ferroptosis as demonstrated by increasing labile iron pool and lipid peroxidation levels as well as Acsl4, TFR1, and HO-1 mRNA and protein levels, decreasing GPX4 and FTH mRNA and protein expressions, and inducing mitochondrial injury. The FXR activator (GW4064) rescued the accumulation of lipid peroxides, intracellular ROS, and Fe2+, inhibited Ferroptosis, and alleviated OTA-induced nephrotoxicity. The Ferroptosis inhibitor (Fer-1) prevented Ferroptosis and attenuated nephrotoxicity. Collectively, this study elucidates that FXR played a critical role in OTA-induced nephrotoxicity via regulation of Ferroptosis, which provides a novel strategy against OTA-induced nephrotoxicity.

Keywords

FXR; OTA; ferroptosis; lipid peroxidation; nephrotoxicity.

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