Notch signaling modulates proliferative vitreoretinopathy via regulating retinal pigment epithelial-to-mesenchymal transition.
Elevated Notch signaling has been verified in a large range of fibrotic diseases developed in the kidney, liver, and lung, inducing the development of the epithelial-mesenchymal transition (EMT). The aim of this study was to observe the involvement of Notch signaling in the EMT of retinal pigment epithelial (RPE) cells and the pathogenesis of proliferative vitreoretinopathy (PVR). In vitro cultivated human RPE cells (ARPE-19) were treated with 10 ng/mL transforming growth factor (TGF)-β1 for 24, 48, and 72 h. The expression levels of ZO-1, α-SMA, vimentin, Notch1 intracellular domain (NICD1), and Hes-1 were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining or Western blot. TGF-β1 induced EMT and the activation of Notch signaling in ARPE-19 cells. To examine the effect of Notch inhibition on TGF-β1-induced EMT and PVR formation, ARPE-19 cells were preincubated with γ-secretase inhibitor LY411575 before TGF-β1 treatment. Mouse PVR model was used for in vivo study. ARPE-19 cells were injected intravitreously with or without the LY411575 to examine the effect of Notch inhibition on PVR formation. LY411575 significantly attenuated EMT by inhibiting the Notch signaling activation in vitro. PVR was induced by intravitreal injections of ARPE-19 cells, while LY411575 inhibited mouse PVR formation in vivo. Notch signaling plays a critical role in TGF-β1-induced EMT in vitro and mice PVR model, which provides a novel insight into the pathogenesis of PVR. The specific inhibition of Notch signaling by γ-secretase inhibitor may provide a new approach for the prevention of PVR.
Shandong Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, 372 Jingsi Road, Jinan, 250021, China.
Jingjing
J
Zhang
Shandong Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, 372 Jingsi Road, Jinan, 250021, China.
Gongqiang
G
Yuan
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, 266071, Shandong Province, China.
Muchen
M
Dong
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, 266071, Shandong Province, China.
Ting
T
Zhang
Shandong Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, 372 Jingsi Road, Jinan, 250021, China.
Gao
G
Hua
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, 266071, Shandong Province, China. qjzhou2000@hotmail.com.
Qingjun
Q
Zhou
Shandong Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, 372 Jingsi Road, Jinan, 250021, China. weiyunshi1@163.com.
Weiyun
W
Shi
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism* / Q000473:pathology*
D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D051881:Receptor, Notch1; D000409:Alanine
Epithelial–mesenchymal transition; Notch signaling; Proliferative vitreoretinopathy; Retinal pigment epithelial cells; Wound healing