Involvement of endoplasmic reticulum stress-activated PERK-eIF2α-ATF4 signaling pathway in T-2 toxin-induced apoptosis of porcine renal epithelial cells

• Published in: Toxicology and applied pharmacology 2021-12, Vol.432, p.115753, Article 115753
• Main Authors: Liu, Xiangyan, Wang, Ze, Wang, Xianglin, Yan, Xiaona, He, Qing, Liu, Sha, Ye, Mengke, Li, Xiaowen, Yuan, Zhihang, Wu, Jing, Yi, Jine, Wen, Lixin, Li, Rongfang
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Caspase 12 - metabolism; Cell Line; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Chaperone BiP - metabolism; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; Eukaryotic Initiation Factor-2 - metabolism; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - enzymology; Kidney Diseases - pathology; Oxidative Stress - drug effects; PK-15 cells; Signal Transduction; Sus scrofa; T-2 Toxin; T-2 Toxin - toxicity; Transcription Factor CHOP - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2021.115753

T-2 toxin is a highly toxic trichothecene that can induce toxic effects in a variety of organs and tissues, but the pathogenesis of its nephrotoxicity has not been elucidated. In this study, we assessed the involvement of protein kinase RNA-like ER kinase (PERK)-mediated endoplasmic reticulum (ER) stress and apoptosis in PK-15 cells cultured at different concentrations of T-2 toxin. Cell viability, antioxidant capacity, intracellular calcium (Ca2+) content, apoptotic rate, levels of ER stress, and apoptosis-related proteins were studied. T-2 toxin inhibited cell proliferation; increased the apoptosis rate; and was accompanied by increased cleaved caspase-3 expression, altered intracellular oxidative stress marker levels, and intracellular Ca2+ overloading. The ER stress inhibitor 4-phenylbutyrate (4-PBA) and PERK selective inhibitor GSK2606414 prevented the decrease of cell activity and apoptosis caused by T-2 toxin. The altered expression of glucose regulatory protein 78 (GRP78), C/EBP homologous protein (CHOP), and caspase-12 proved that ER stress was involved in cell injury triggered by T-2 toxin. T-2 toxin activated the phosphorylation of PERK and the alpha subunit of eukaryotic initiation factor 2 (eIF2α) and upregulated the activating transcription factor 4 (ATF4), thereby triggering ER stress via the GRP78/PERK/CHOP signaling pathway. This study provides a new perspective for understanding the nephrotoxicity of T-2 toxin. [Display omitted] •T-2 toxin induced apoptosis in a dose-dependent manner.•Oxidative stress was indicated after T-2 toxin exposure.•ER stress aggravated T-2 toxin-induced apoptosis in PK-15 cells.•T-2 toxin activated the PERK-eIF2α-ATF4 axis of the UPR.