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Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation

Zhang, Yimeng, Xu, Youwei, Qi, Yan, Xu, Lina, Song, Shasha, Yin, Lianhong, Tao, Xufeng, Zhen, Yuhong, Han, Xu, Ma, Xiaodong, Liu, Kexin, Peng, Jinyong
Toxicology 2017 v.378 pp. 53-64
agonists, chromium, doxorubicin, electrostatic interactions, glutathione peroxidase, hydrogen bonding, hydrophobicity, in vivo studies, inflammation, interleukin-1beta, interleukin-6, ischemia, kidneys, messenger RNA, molecular models, nephrotoxicity, nucleoproteins, oxidative stress, protective effect, rats, small interfering RNA, superoxide dismutase, transcription factor NF-kappa B, tumor necrosis factor-alpha
Dioscin shows active effects against renal ischemia/reperfusion injury and lipopolysaccharide-induced inflammatory kidney injury, however, little is known concerning the role of it on doxorubicin (Dox)-induced nephrotoxicity. In the present study, in vivo test of Dox-induced nephrotoxicity in rats and in vitro model in NRK-52E cells were developed. The results showed that dioscin significantly attenuated cell injury, obviously reduced ROS level in vitro, and markedly decreased the levels of BUN, Cr, MDA, and notably increased the levels of SOD, GSH and GSH-Px in rats. Mechanistic studies showed that dioscin significantly increased the levels of p-AMPKα, Nrf2, HO-1 and GST by activation of FXR against oxidative stress. In addition, dioscin suppressed the nuclear translocation of NF-κB and HMGB1, and subsequently decreased the mRNA levels of IL-1β, IL-6, and TNF-α against inflammation. These results were further validated by knockdown of FXR using siRNA silencing, and abrogation of FXR using NDB (a FXR inhibitor) in NRK-52E cells, and the results suggested that the protective effect of dioscin against Dox- induced nephrotoxicity via adjusting FXR-mediated signal to suppress oxidative stress and inflammation. In addition, molecular docking assay showed that dioscin directly targeted with FXR through competing with Helix12 (H12) by hydrogen bonding, hydrophobic effect and electrostatic interactions. In a word, our data showed that dioscin is a novel and potent FXR agonist to suppress inflammation and oxidative stress against Dox-induced nephrotoxicity.