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

Abstract

Dioscin exhibits a range of pharmacological actions but little is known of its effects on cisplatin (CDDP)-induced nephrotoxicity. Here, we have assessed the effects and the possible mechanisms of dioscin against CDDP-induced nephrotoxicity. We used an in vivo model of CDDP-induced nephrotoxicity in rats and mice and, in vitro, cultures of NRK-52E and HK-2 cells. The dual luciferase reporter assay was used to demonstrate modulation, by dioscin, of the targeting of sirtuin 1 (Sirt1) by microRNA (miR)-34a. Molecular docking assays were used to analyse the effects of dioscin with Sirt1, Keap1 and NF-κB. Dioscin attenuated cell damage in vitro and decreased renal injury in rats and mice, treated with CDDP. In terms of mechanisms, dioscin reversed CDDP-induced up-regulation of miR-34a and thus up-regulated Sirt1 levels. In addition, dioscin altered levels of haem oxygenase 1, glutathione-cysteine ligase subunits (GCLC, GCLM) and Keap1, along with increased nuclear translocation of Nrf2, thus decreasing oxidative stress. Also, dioscin affected levels of AP-1, COX-2, HMGB1, IκB-α, IL-1β, IL-6 and TNF-α and decreased the ratio of acetylated NF-κB and normal NF-κB, to suppress inflammation. From molecular docking assays, dioscin directly bound to Sirt1, Keap1 and NF-κBp65 by hydrogen bonding and/or hydrophobic interactions. Our results have linked CDDP-induced nephrotoxicity and the miR-34a/Sirt1 signalling pathway, which was modulated by dioscin. This natural product could be developed as a new candidate to alleviate CDDP-induced renal injury.