Abstract
Background and AimProliferative vitreoretinopathy (PVR) is an active process that develops as a complication upon retinal detachment (RD), accompanied by formation of fibrotic tissue. The main cells involved in the development of fibrotic tissue during PVR are the retinal pigment epithelial (RPE) cells. The RPE cells undergo epithelial-mesenchymal transition (EMT) which leads to complex retinal detachment and loss of vision. Transforming growth factor-β1 (TGF-β1) is considered as the main player in the EMT of RPE cells, even though the mechanism is not fully understood. This study was performed to determine the possible involvement of transforming growth factor β activated kinase 1 (TAK1) in the EMT process of the RPE cells.MethodologyARPE-19 Cells were treated with 5Z-7 oxozeaenol (TAK1 inhibitor) or SB431542 (TGF-β1 receptor kinase inhibitor) followed by TGF-β1 stimulation. Immunofluorescence, scratch assay Real time PCR and collagen contraction assay assessed the EMT features. The phosphorylation of Smad2/3 and p38 was examined using western blots analysis.ResultsThis study demonstrates that stimulation of RPE cells with TGF-β1 increases α-SMA expression, cell migration and cell contractility, all of which are EMT features. Remarkably, addition of TAK1 inhibitor abolishes all these processes. Furthermore, we show hereby that TAK1 regulates not only the activation of the non-canonical cascade of TGF-β1 (p38), but also the canonical cascade, the Smad2/3 activation. Thus, the outcome of the TGF-β response in RPE cells is TAK1 dependent.Conclusions/SignificanceThis work demonstrated TAK1, a component of the non-canonical pathway of TGF-β1, is a key player in the EMT process, thus provides deep insight into the pathogenesis of PVR. The ability to halt the process of EMT in RPE cells may reduce the severity of the fibrotic response that occurs upon PVR, leading to a better prognosis and increase the probability of success in RD treatment.
Highlights
Proliferative vitreoretinopathy (PVR) is an active process that develops as a complication during retinal detachment (RD) and it is the most common cause of surgical failure upon RD treatment [1]
This study demonstrates that stimulation of retinal pigment epithelial (RPE) cells with Transforming growth factor-β1 (TGF-β1) increases α-SMA expression, cell migration and cell contractility, all of which are epithelial-mesenchymal transition (EMT) features
To address a possible involvement of transforming growth factor β activated kinase 1 (TAK1) in TGF-β1-induced RPE cells transdifferentiation, we studied the effects of specific TAK1 inhibitor on this process
Summary
Proliferative vitreoretinopathy (PVR) is an active process that develops as a complication during retinal detachment (RD) and it is the most common cause of surgical failure upon RD treatment [1]. During PVR, RPE cells undergo transformation into fibroblast-like cells through a process known as the epithelial-mesenchymal transition (EMT) [3]. Proliferative vitreoretinopathy (PVR) is an active process that develops as a complication upon retinal detachment (RD), accompanied by formation of fibrotic tissue. The main cells involved in the development of fibrotic tissue during PVR are the retinal pigment epithelial (RPE) cells. The RPE cells undergo epithelial-mesenchymal transition (EMT) which leads to complex retinal detachment and loss of vision. This study was performed to determine the possible involvement of transforming growth factor β activated kinase 1 (TAK1) in the EMT process of the RPE cells
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