Abstract
The epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a central role in the development of proliferative vitreoretinopathy (PVR). The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF)-α (10 ng/ml) and transforming growth factor (TGF)-β2 (5 ng/ml). 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), a potent activator of AMPK, significantly suppressed TNF-α and TGF-β2-induced cellular aggregate formation (p < 0.01). Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5’-amino-5’-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and α-smooth muscle actin by TNF-α and TGF-β2. The levels of matrix metalloproteinase (MMP)-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy.
Highlights
Proliferative vitreoretinopathy (PVR) is one of the severe complications that can arise after rhegmatogenous retinal detachment surgery or ocular trauma
It has been reported that stimulation of ARPE-19 cells with both tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β2 leads to formation of cellular aggregates that have been termed epithelial-mesenchymal transition (EMT)-associated fibrotic deposits [19]
We utilized an in vitro model that involved co-stimulation of Retinal pigment epithelial (RPE) cell monolayers with TNF-α and TGF-β2, resulting in the formation of cellular aggregates, and we demonstrated that AICAR almost completely suppressed this phenomenon
Summary
Proliferative vitreoretinopathy (PVR) is one of the severe complications that can arise after rhegmatogenous retinal detachment surgery or ocular trauma. PVR is characterized by the formation of contractile fibrous membranes that cause severe tractional retinal detachment and make it difficult to reattach the retina [1]. The EMT plays a central role in the development of PVR, during which RPE cells undergo the EMT and transdifferentiate into myofibroblasts expressing αsmooth muscle actin (α-SMA) that produces a contractile force [7,8,9,10]. Suppressing EMT of RPE cells is considered to be a potential treatment strategy for PVR
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