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

Abstract

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.

• Authors: Yimeng Zhang, Youwei Xu, Yan Qi, Lina Xu, Shasha Song, Lianhong Yin, Xufeng Tao, Yuhong Zhen, Xu Han, Xiaodong Ma, Kexin Liu, Jinyong Peng
• Journal: Toxicology (Toxicology) Vol. 378 Pg. 53-64 (03 01 2017) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 28082111 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, rat
• Protective Agents
• Reactive Oxygen Species
• Receptors, Cytoplasmic and Nuclear
• farnesoid X-activated receptor
• dioscin
• Doxorubicin
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat
• Glutathione Transferase
• AMP-Activated Protein Kinases
• Diosgenin

Topics

• AMP-Activated Protein Kinases (genetics)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Cell Line
• Cell Survival (drug effects)
• Cytokines (genetics)
• Diosgenin (analogs & derivatives, pharmacology, therapeutic use)
• Doxorubicin
• Glutathione Transferase (metabolism)
• Heme Oxygenase (Decyclizing) (metabolism)
• Kidney (drug effects, metabolism, pathology)
• Kidney Diseases (chemically induced, drug therapy, metabolism, pathology)
• Male
• Molecular Docking Simulation
• NF-E2-Related Factor 2 (genetics)
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Protective Agents (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Receptors, Cytoplasmic and Nuclear (agonists, genetics, metabolism)