Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway.
Cisplatin is one of the most effective chemotherapeutic agents; however, its clinical use is limited by serious side effects of which nephrotoxicity is the most important. Nephrotoxicity induced by cisplatin is closely associated with autophagy reduction and caspase activation. In this study, we investigated whether neferine, an autophagy inducer, had a protective effect against cisplatin-induced nephrotoxicity. In an in vitro cisplatin-induced nephrotoxicity model, we determined that neferine was able to induce autophagy and that pretreatment with neferine not only attenuated cisplatin-induced cell apoptosis but further activated cell autophagy. This pro-survival effect was abolished by the autophagic flux inhibitor chloroquine. Furthermore, neferine pretreatment activated the AMPK/mTOR pathway; however, pharmacological inhibition of AMPK abolished neferine-mediated autophagy and nephroprotection against cisplatin-induced apoptosis. Collectively, our findings suggest for the first time the possible protective mechanism of neferine, which is crucial for its further development as a potential therapeutic agent for cisplatin-induced nephrotoxicity.
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Hui
H
Li
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Yuling
Y
Tang
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Long
L
Wen
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Xianglong
X
Kong
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Xuelian
X
Chen
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Ping
P
Liu
Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan, China.
Zhiguo
Z
Zhou
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Wenhang
W
Chen
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Chenggen
C
Xiao
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: xiaoping.x@163.com.
Ping
P
Xiao
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: 38332645@qq.com.
Xiangcheng
X
Xiao
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001343:Autophagy / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000008:administration & dosage*; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; C057222:neferine; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002945:Cisplatin
Apoptosis; Autophagy; Cell signaling; Cisplatin nephrotoxicity; NRK52-E cell; Neferine