Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling.
Reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelial (RPE) cells, which is known as one major cause of age-related macular degeneration. Salvianolic acid A (Sal A) is the main effective aqueous extract of Salvia miltiorrhiza. The aim of this study was to test the potential role of Sal A against oxidative stress in cultured RPE cells and to investigate the underlying mechanistic signaling pathways. We observed that Sal A significantly inhibited hydrogen peroxide (H2O2)-induced primary and transformed RPE cell death and apoptosis. H2O2-stimulated mitogen-activated protein kinase activation, ROS production, and subsequent proapoptotic AMP-activated protein kinase activation were largely inhibited by Sal A. Further, Sal A stimulation resulted in a fast and dramatic activation of Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, followed by phosphorylation, accumulation, and nuclear translocation of the NF-E2-related factor 2 (Nrf2), along with increased expression of the antioxidant-response element-dependent gene heme oxygenase-1 (HO-1). Both Nrf2 and HO-1 were required for Sal A-mediated cytoprotective effect, as Nrf2/HO-1 inhibition abolished Sal A-induced beneficial effects against H2O2. Meanwhile, the PI3K/Akt/mTORC1 chemical inhibitors not only suppressed Sal A-induced Nrf2/HO-1 activation, but also eliminated its cytoprotective effect in RPE cells. These observations suggest that Sal A activates the Nrf2/HO-1 axis in RPE cells and protects against oxidative stress via activation of Akt/mTORC1 signaling.
The Eye Hospital, Nanjing Medical University, Nanjing 210029, China.
Hui
H
Zhang
Institute of Neuroscience, Soochow University, Suzhou 215123, China.
Yuan-yuan
YY
Liu
The Eye Hospital, Nanjing Medical University, Nanjing 210029, China.
Qin
Q
Jiang
The Eye Hospital, Nanjing Medical University, Nanjing 210029, China.
Ke-ran
KR
Li
The Eye Hospital, Nanjing Medical University, Nanjing 210029, China.
Yu-xia
YX
Zhao
The Eye Hospital, Nanjing Medical University, Nanjing 210029, China; Institute of Neuroscience, Soochow University, Suzhou 215123, China. Electronic address: caocong@suda.edu.cn.
Cong
C
Cao
The Eye Hospital, Nanjing Medical University, Nanjing 210029, China. Electronic address: dryaojin@yahoo.com.
Jin
J
Yao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002109:Caffeic Acids / Q000008:administration & dosage*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007773:Lactates / Q000008:administration & dosage*; D008268:Macular Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D002109:Caffeic Acids; D007773:Lactates; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C066201:salvianolic acid A; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
Age-related macular degeneration; Akt/mTOR; Free radicals; HO-1; Nrf2; Oxidative stress; Salvianolic acid A