title: 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.
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Moon
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Jong-Bin
authors.initials: JB
authors.lastname: Kim
authors.forename: Nam-In
authors.initials: NI
authors.lastname: Baek
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
authors.forename: Yong Sup
authors.initials: YS
authors.lastname: Lee
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Kay
authors.forename: Soo-dong
authors.initials: SD
authors.lastname: Kim
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D001806:Blood Urea Nitrogen; D029741:Brassica rapa / Q000737:chemistry; D002460:Cell Line / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects*; D003404:Creatinine / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C000597749:6-hydroxy-1-methylindole-3-acetonitrile; D007211:Indoles; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D020011:Protective Agents; D017382:Reactive Oxygen Species; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D005978:Glutathione; D002945:Cisplatin
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