Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress.
Here we explored the anti-oxidative and cytoprotective potentials of escin, a natural triterpene-saponin, against hydrogen peroxide (H2O2) in retinal pigment epithelium (RPE) cells. We showed that escin remarkably attenuated H2O2-induced death and apoptosis of established (ARPE-19) and primary murine RPE cells. Meanwhile, ROS production and lipid peroxidation by H2O2 were remarkably inhibited by escin. Escin treatment in RPE cells resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by transcription of anti-oxidant-responsive element (ARE)-regulated genes, including HO-1, NQO-1 and SRXN-1. Knockdown of Nrf2 through targeted shRNAs/siRNAs alleviated escin-mediated ARE gene transcription, and almost abolished escin-mediated anti-oxidant activity and RPE cytoprotection against H2O2. Reversely, escin was more potent against H2O2 damages in Nrf2-over-expressed ARPE-19 cells. Further studies showed that escin-induced Nrf2 activation in RPE cells required AKT signaling. AKT inhibitors (LY294002 and perifosine) blocked escin-induced AKT activation, and dramatically inhibited Nrf2 phosphorylation, its cytosol accumulation and nuclear translocation in RPE cells. Escin-induced RPE cytoprotection against H2O2 was also alleviated by the AKT inhibitors. Together, these results demonstrate that escin protects RPE cells from oxidative stress possibly through activating AKT-Nrf2 signaling.
Eye Center, The 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China.
Kaijun
K
Wang
The First People Hospital of Xiaoshan, Hangzhou, China.
Yiqian
Y
Jiang
Eye Center, The 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China.
Wei
W
Wang
Eye Center, The 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China.
Jian
J
Ma
Eye Center, The 2nd Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China. Electronic address: eyedrchenminzj@163.com.
Min
M
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004928:Escin / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D004928:Escin; D051057:Proto-Oncogene Proteins c-akt
AKT and Nrf2 signaling; Escin; Oxidative stress; Retinal pigment epithelium cells