Protective effects of 6-hydroxy-1-methylindole-3-acetonitrile on cisplatin-induced oxidative nephrotoxicity via Nrf2 inactivation

Abstract

We previously demonstrated the ethanol extract of the roots of Brassica rapa protects against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Here, we investigated the nephroprotective effects of 6-hydroxy-1-methylindole-3-acetonitrile (6-HMA), which was isolated from the roots of B. rapa, on cisplatin-induced toxicity in renal epithelial LLC-PK1 cells and in rats with acute renal injury. Pretreatment of LLC-PK1 cells with 6-HMA ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased levels of glutathione (GSH). In addition, 6-HMA inhibited cisplatin-induced heme oxygenase-1 (HO-1) expression, possibly due to the suppression of the nuclear translocation and binding activity of NF-E2-related factor 2 (Nrf2). Furthermore, 6-HMA administered rats showed lower levels of blood urea nitrogen (BUN), creatinine, and urinary lactate dehydrogenase (LDH) than cisplatin alone-treated rats in cisplatin-induced renal injury model. Moreover, 6-HMA inhibited the cisplatin-induced formation of MDA and GSH depletion and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). Taken together, these findings indicate 6-HMA is a major active constituent from the roots of B. rapa to have a protective effect against cisplatin-induced nephrotoxicity by attenuating oxidative stress.

Keywords: 1-MA; 1-methoxyindole-3-acetonitrile; 2,7-dichlorofluorescein diacetate; 6-HMA; 6-Hydroxy-1-methylindole-3-acetonitrile; 6-hydroxy-1-methylindole-3-acetonitrile; ARE; BUN; CAT; DCFH-DA; DMSO; EMSA; EtOAc; FBS; GR; GSH; Glutathione reductase; HO-1; LDH; MDA; N-acetyl-L-cysteine; NAC; NF-E2-related factor 2; Nephrotoxicity; Nrf2; PBS; ROS; SDS; SOD; TBA; TBA-reactive substances; TBARS; antioxidant response element; blood urea nitrogen; catalase; dimethyl sulfoxide; electrophoretic mobility shift assay; ethyl acetate; fetal bovine serum; glutathione; heme oxygenase-1; lactate dehydrogenase; malondialdehyde; phosphate-buffered saline; reactive oxygen species; sodium dodecyl sulfate; superoxide dismutase; thiobarbituric acid.