Protective effects of dioscin against cisplatin-induced nephrotoxicity via the microRNA-34a/sirtuin 1 signalling pathway

Background and Purpose Dioscin has various pharmacological actions in our previous works, however, little is known concerning the role of it on cisplatin (CDDP)-induced nephrotoxicity. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against CDDP-induced nephrotoxicity. Experimental Approach In the present study, the in vivo models of CDDP-induced nephrotoxicity in rats and mice were used, and the in vitro models on NRK-52E and HK-2 cells were developed. In mechanism investigation, dual luciferase reporter assay was used to validate the modulation of miR-34a via targeting Sirt1 by dioscin. Molecular docking assay was used to detect the effect of dioscin with Sirt1, Keap1 and NF-κB. Key Results Dioscin significantly attenuated cell damages in vitro, and obviously restored renal injury in rats and mice compared with model groups. Mechanism study showed that dioscin significantly reversed CDDP-induced up-regulation of miR-34a, then up- regulated Sirt1 level. In addition, dioscin significantly regulated the levels of HO-1, GCLC, GCLM and Keap1 by increasing the nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin obviously regulated the levels of AP-1, COX-2, HMGB1, IKB-α, IL-1β, IL-6, TNF-α, and decreased the ratios of acetylated NF-κB and normal NF-κB to suppress inflammation. In addition, dioscin directly targeted with Sirt1, Keap1 and NF-κBp65 by hydrogen bonding and/or hydrophobic effect. Conclusions and Implications In conclusion, our results support a link between CDDP-induced nephrotoxicity and miR-34a/Sirt1 signal pathway, which can be modulated by dioscin. This natural product should be developed as a new candidate to alleviate CDDP-induced renal injury in trial in future.