Betulinic acid attenuates T-2 toxin-induced cytotoxicity in porcine kidney cells by blocking oxidative stress and endoplasmic reticulum stress.

T-2 toxin is highly cytotoxic to animals, which causes damage to animal health and great economic losses to agriculture and livestock production. Betulinic acid (BA), a naturally occurring pentacyclic lupane-type triterpenoid, has various biological and medicinal activities in vivo and in vitro. The objective of the present study was to investigate the toxic effects of T-2 toxin and the reversal effect of BA on porcine kidney (PK-15) cells. We evaluated T-2 toxin-induced apoptotic responses via oxidative stress and endoplasmic reticulum stress pathways by assessing the repair effect of BA in PK-15 cells. The results proved that T-2 toxin (1 μM, treated for 24 h) is highly toxic to PK-15 cells. After pre-treatment with BA (0.25, 0.5, and 1 μM) for 24 h, the cell viabilities were significantly increased, and the lactate dehydrogenase (LDH) in the culture media was dramatically decreased compared to that in the T-2 toxin treatment group. BA also enhanced the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and catalase (CAT) and reduced the production of reactive oxygen species (ROS) and malondialdehyde (MDA) in cells. BA also dose-dependently increased the expression of glucose regulated protein (GRP78), reduced expression of activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2α (eIF2α), and intracellular Ca concentration in a dose-dependent manner. In addition, BA significantly decreased the expression of cleaved-caspase-3 and caspase-12, consequently reducing T-2 toxin-induced PK-15 cell apoptosis in a dose-dependent manner. Collectively, we suggest that BA has a protective effect on T-2 toxin-induced cytotoxicity by ameliorating oxidative stress and endoplasmic reticulum stress in PK-15 cells.