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.