Blockade of Jagged/Notch Pathway Abrogates Transforming Growth Factor β2-Induced Epithelial-Mesenchymal Transition in Human Retinal Pigment Epithelium Cells
The epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays a key
role in proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), which lead to the loss
of vision. The Jagged/Notch pathway has been reported to be essential in EMT during embryonic
development, fibrotic diseases and cancer metastasis. However, the function of Jagged/Notch signaling in
EMT of RPE cells is unknown. Thus, we hypothesized that a crosstalk between Notch and transforming growth
factor β2 (TGF-β2) signaling could induce EMT in RPE cells, which subsequently contributes to PVR and PDR.
Here, we demonstrate that Jagged-1/Notch pathway is involved in the TGF-β2-mediated EMT of human RPE
cells. Blockade of Notch pathway with DAPT (a specific inhibitor of Notch receptor cleavage) and knockdown
of Jagged-1 expression inhibited TGF-β2-induced EMT through regulating the expression of Snail, Slug and
ZEB1. Besides the canonical Smad signaling pathway, the noncanonical PI3K/Akt and MAPK pathway also
contributed to TGF-β2-induced up-regulation of Jagged-1 in RPE cells. Overexpression of Jagged-1 could
mimic TGF-β2 induce EMT. Our data suggest that the Jagged-1/Notch signaling pathway plays a critical role in
TGF-β2-induced EMT in human RPE cells, and may contribute to the development of PVR and PDR. Inhibition
of the Jagged/Notch signaling pathway, therefore, may have therapeutic value in the prevention and treatment
of PVR and PDR.
Keywords: Epithelial-mesenchymal transition (EMT), Jagged/Notch signaling, proliferative diabetic retinopathy
(PDR), proliferative vitreoretinopathy (PVR), retinal pigment epithelium (RPE) cells.
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