Ochratoxin A Induces Nephrotoxicity in Vitro And in Vivo Via Pyroptosis

Overview

Journal Arch Toxicol

Specialty Toxicology

Date 2021 Feb 5

PMID 33543323

Citations 18

Authors

Hu Li

Xinru Mao

Kai Liu

Jiahao Sun

Benrui Li

Rahmani Mohammad Malyar

Dandan Liu

Cuiling Pan

Fang Gan

Yunhuan Liu

Kehe Huang

Xingxiang Chen

Affiliations

Soon will be listed here.

Abstract

Ochratoxin A (OTA), a prevalent nephrotoxic mycotoxin contaminant in food and feedstuff, has been reported to induce renal injury. To disclose the nephrotoxicity of continuous administration of OTA and to investigate potential mechanisms related to pyroptosis, male C57BL/6 mice were intraperitoneally injected with 1.0 and 2.0 mg/kg B.W. OTA every other day for 14 days. At 2.0 mg/kg B.W. OTA administration significantly increased histological injury and renal fibrosis molecules (α-SMA, Vimentin, TGF-β) and activated the NOD-like receptor protein 3 (NLRP3) inflammasome and induced pyroptosis compared with control. In the in vitro tests, Madin-Darby canine kidney (MDCK) epithelial cells were exposed to 0-4.0 μg/ml OTA for 24 h in serum-free medium. Data showed that OTA dose-dependently affected cell viability and significantly up-regulated renal fibrosis genes (α-SMA, Vimentin, TGF-β). 2.0 μg/ml OTA significantly induced NLRP3 inflammasome activation and caspase-1-dependent pyroptosis, increasing the expression and secretion of pro-inflammatory cytokines (IL-6, TNF-α) and pyroptosis-related genes (GSDMD, IL-1β, IL-18) in MDCK cells. These outcomes were significantly abrogated after inhibiting NLRP3 activation with inhibitor MCC950 and silencing NLRP3 with small interfering RNA (siRNA). Furthermore, knockdown of caspase-1 also ameliorated OTA-induced renal fibrosis via the inhibition of pyroptosis. Collectively, the chosen doses of OTA-triggered nephrotoxicity through NLRP3 inflammasome activation and caspase-1-dependent pyroptosis both in vitro and in vivo.

Citing Articles

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