Ochratoxin A induces glomerular injury through activating the ERK/NF-κB signaling pathway

• Published in: Food and chemical toxicology 2020-09, Vol.143, p.111516, Article 111516
• Main Authors: Le, Guannan, Yuan, Xin, Hou, Lili, Ge, Lei, Liu, Shuiping, Muhmood, Azhar, Liu, Kai, Lin, Ziman, Liu, Dandan, Gan, Fang, Song, Suquan, Pan, Cuilin, Chen, Xingxiang, Huang, Kehe
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Survival; Cytokines - genetics; Cytokines - metabolism; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation - drug effects; Glomerular injury; Human mesangial cells; Humans; Kidney Glomerulus - drug effects; Male; Mesangial Cells - drug effects; Mice; Mice, Inbred C57BL; NF-kappa B - genetics; NF-kappa B - metabolism; Ochratoxin A; Ochratoxins - administration & dosage; Ochratoxins - toxicity; Random Allocation; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; The ERK/NF-κB signaling pathway
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2020.111516

Ochratoxin A (OTA) was reported to induce proximal tubules nephrotoxicity in humans and animals. However, the toxicity of OTA on glomeruli has rarely been studied. We investigated OTA-induced glomerular injury and the underlying mechanisms. Mice were intraperitoneally treated with OTA (0, 0.5, 1.5 and 2.5 mg/kg b.w.) on alternate day for 3 weeks. OTA exposure decreased the weight gain ratio, the kidney index and increased the levels of serum creatinine and blood urea nitrogen. It induced also fragmentation and atrophy in glomeruli, and increased the expression of TNF-α, IL-6, COX-2, TGF-β, α-SMA and vimentin in a dose-dependent manner. Human mesangial cells (HMC) were treated with OTA (0–8 μM) for 48 h. Treatment of HMC cells with OTA increased cell inhibition rate, up-regulated the expression of IL-6, TGF-β, α-SMA and vimentin in a dose-dependent manner. Additionally, it enhanced the phosphorylation of ERK1/2 and p65, degradation of IκB-α and translocation of p65 into the nucleus. OTA-induced toxicity was attenuated by NF-κB and ERK1/2 inhibitors. In conclusion, these results suggest that OTA exposure induces glomerular injury via activation of the ERK/NF-κB signaling pathway, and provide novel insights into the research of OTA induced nephrotoxicity. Proposed scheme of OTA induced glomerular injury. OTA exposure induces glomerular injury in mice and cytotoxicity in HMC cells in a dose-dependent manner via activation of the ERK/NF-κB axis. [Display omitted] •Ochratoxin A induced glomerular injury in mice and cytotoxicity in Human mesangial cells.•Ochratoxin A increased the expression of inflammatory and fibrosis biomarkers in vivo and in vitro.•Toxicity induced by ochratoxin A via activating the ERK/NF-κB axis.•Inhibition of the ERK/NF-κB axis by inhibitors weaken OTA-induced toxicity in Human mesangial cells.