Activation of the NRF2-ARE signalling pathway by the Lentinula edodes polysaccharose LNT alleviates ROS-mediated cisplatin nephrotoxicity.
The nephrotoxicity of cisplatin (cis-DDP) limits its general clinical applications. Lentinan (LNT), a dextran extracted from the mushroom Lentinula edodes, has been shown to have multiple pharmacological activities. The primary objective of the current study was to determine whether and how LNT alleviates cis-DDP- induced cytotoxicity in HK-2 cells and nephrotoxicity in mice. LNT did not interfere with cisplatin's anti-tumour efficacy in vitro and functioned cooperatively with cis-DDP to inhibit activity in HeLa and A549 tumour cells. LNT alleviated the cis-DDP-induced decrease in HK-2 cell viability, caspase-3 activation and cleavage of the DNA repair enzyme PARP, decreased HK-2 cell apoptosis and inhibited reactive oxygen species (ROS) accumulation in HK-2 cells. The inhibitor of ROS (N-acetyl-L-cysteine, NAC) could decreased the apoptosis of HK-2 cell. In addition, LNT significantly prevented cis-DDP-induced kidney injury in vivo. LNT itself could not eliminate ROS levels in vitro. Further studies demonstrated that LNT induced NF-E2 p45-related factor 2 (Nrf2) protein and mRNA expression in a time- and dose-dependent manner. LNT promoted Nrf2 translocation to the nucleus and binding to the antioxidant-response element (ARE) sequence and induced the transcription and translation of heme oxygenase 1 (HO-1), aldo-keto reductases 1C1 and 1C2 (AKR1C), and NADP(H):quinone oxidoreductase 1 (NQO1). Finally, we used hNrf2 siRNA and an Nrf2 agonist (tBHQ) to inhibit or enhance Nrf2 expression. The results demonstrated that the LNT-mediated alleviation of cis-DDP-induced nephrotoxicity was achieved by preventing the accumulation of ROS in a manner that depended on the activation of the Nrf2-ARE signalling pathway.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Qian
Q
Chen
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Huixia
H
Peng
Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Lei
L
Dong
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Lijuan
L
Chen
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Xiaobin
X
Ma
Department of Radiology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Yuping
Y
Peng
Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China. Electronic address: Daishejiao@qq.com.
Shejiao
S
Dai
Department of Radiology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China. Electronic address: liuqiang332211@sohu.com.
Qiang
Q
Liu
D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007912:Lentinan / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020942:Shiitake Mushrooms; D015398:Signal Transduction / Q000187:drug effects
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D007912:Lentinan; D006861:Hydrogen Peroxide; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D002945:Cisplatin
Cisplatin; Lentinan; NRF2-ARE signal; Nephrotoxicity; ROS