23-Hydroxytormentic acid and niga-ichgoside F₁ isolated from Rubus coreanus attenuate cisplatin-induced cytotoxicity by reducing oxidative stress in renal epithelial LLC-PK₁ cells

The unripe fruits of Rubus coreanus (Rosaceae) are used in traditional Chinese medicine to relieve kidney dysfunction. In the present study, we evaluated the protective effects of the triterpenoid glycoside niga-ichigoside F₁ (NIF₁) and of its aglycone 23-hydroxytormentic acid (23-HTA) isolated from the unripe fruits of Rubus coreanus (Rosaceae) against cisplatin-induced cytotoxicity in renal epithelial LLC-PK₁ cells. Pretreating LLC-PK₁ cells with 23-HTA or NIF₁ was found to prevent cisplatin-induced cytotoxicity and apoptosis. In addition, 23-HTA or NIF₁ pretreatment significantly improved the changes associated with cisplatin toxicity by increasing levels of glutathione (GSH) and decreasing levels of malondialdehyde (MDA) and reactive oxygen species (ROS). The activity of antioxidant enzymes including catalase (CAT) and superoxide dismutase (SOD) was significantly lower in cisplatin-treated LL-PK₁ cells, and 23-HTA or NIF₁ treatment notably increased the these enzyme activity and protein and mRNA levels of CAT and manganese SOD (MnSOD). Moreover, cisplatin caused a significant decrease in nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and pretreatment with 23-HTA or NIF₁ significantly suppressed the cisplatin-induced translocation of Nrf2 in LLC-PK₁ cells. Taken together, these results suggest that 23-HTA ameliorates cisplatin-induced toxicity via modulation of antioxidant enzymes through activation of Nrf2 in LLC-PK₁ cells.