Abstract
Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells is a major pathologic change in the development of proliferative vitreoretinopathy (PVR), which leads to severe visual impairment. ERK1/2 pathway has been reported to play a key role in the carcinogenesis, cancer metastasis, and multiple fibrotic diseases. We hypothesized that ERK1/2 signaling could cross-interact with transforming growth factor β2 (TGFβ2)/Smad and Notch signaling pathways in the regulation of EMT in RPE cells. Here, we demonstrated that ERK1/2 signaling was activated in TGFβ2-induced EMT in human RPE cells, while blockade of the canonical TGFβ2/Smad2/3 signaling with SB431542 could not inhibit TGFβ2-induced the activation of ERK1/2. Meanwhile, blockade of ERK1/2 signaling with a specific MEK/ERK1/2 inhibitor U0126 strongly prevented TGFβ2-induced the downregulation of P-cadherin, and the upregulation of α-SMA, collagen type IV, N-cadherin and fibronectin in RPE cells. In addition, we also identified that blockade of ERK1/2 signaling could inhibit not only the canonical TGFβ/Smad signaling, but also the Jagged/Notch pathway. Finally, we found that blockade of Notch pathway with a specific inhibitor DAPT could inhibit TGFβ2-induced the activation of ERK1/2 pathway conversely. Therefore, our study provides evidence that ERK1/2 signaling can cross-interact with the canonical TGFβ/Smad and the Jagged/Notch signaling pathways in RPE cells EMT. ERK1/2 inhibitor may have therapeutic value in the prevention and treatment of PVR and other fibrotic diseases.
Highlights
Proliferative vitreoretinopathy (PVR) is a severe complication of retinal detachment (RD) and ocular trauma, and the most common cause of surgical failure in the RD treatment
These results suggest that ERK1/2 signaling can cross-interact with the canonical Transforming growth factor b (TGFb)/Smad and the Jagged/Notch signaling pathways in retinal pigment epithelium (RPE) cells epithelial-mesenchymal transition (EMT)
We examined the role of the ERK1/2 pathway in transforming growth factor b2 (TGFb2)-induced EMT in human RPE cells, with a focus on the interaction of ERK1/2 signaling with the canonical TGFb2/ Smad and the Jagged/Notch pathways
Summary
Proliferative vitreoretinopathy (PVR) is a severe complication of retinal detachment (RD) and ocular trauma, and the most common cause of surgical failure in the RD treatment. Retinal detachment and trauma give rise to the breakdown of the blood-retinal barrier (BRB), through which inflammatory cells, serum cytokines, and growth factors penetrate into the vitreous cavity and/or sub-retinal space [4]. This process allows the body to heal and repair the tissue damage. RPE cells are stimulated to proliferate, undergo EMT, and develop the ability to migrate towards the vitreous body or intraretinal layers through the retinal break During this process, extracellular matrix (ECM) containing collagen and fibronectin are produced, and RPE cells transform into fibroblast-like cells constantly, which further results in the formation of pre- and sub-fibrous membranes [4]. Agents capable of inhibiting the EMT of RPE cells may be of great therapeutic value in the prevention of PVR after retinal reattachment and trauma surgeries
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