Abstract
Müller cells are retinal glial cells and exhibit a fibroblast-like phenotype and ability to migrate in diabetic retinopathy (DR). However, expression of mesenchymal markers, which promote fibrosis in various organs, has not been characterized in the diabetic retina. We examined changes in the expression of these markers in Müller cells exposed to high glucose and in animal models of diabetic retinopathy. High glucose conditions increased mesenchymal maker expression and migration in Müller cells. Snail, N-cadherin, Vimentin, β-catenin, and α-smooth muscle actin (α-SMA) levels were all dramatically increased in retinas from humans with diabetic retinopathy (DR) and from DR mouse models. In addition, Snail overexpression increased the expression of connective tissue growth factor (CTGF) and fibronectin, while Snail knockdown attenuated high glucose-induced increases in fibronectin and CTGF expression. These results demonstrate for the first time that mesenchymal markers are upregulated in retinas from a diabetic mouse model, and that Snail and N-cadherin levels are also increased in Müller cells exposed to high glucose. This suggests mesenchymal proteins may play a crucial role in the development of DR.
Highlights
Diabetic retinopathy (DR) is a severe complication of diabetes and the leading cause of blindness among working adults worldwide [1]
Immunostaining revealed that vimentin, N-cadherin, α-smooth muscle actin (α-SMA), and Snail were expressed in epiretinal membranes from PDR patients
N-cadherin, α-SMA, and Snail levels were higher in retinas from diabetic mice, and these mesenchymal markers partially colocalized with the Müller cell marker GS (Figure 2C)
Summary
Diabetic retinopathy (DR) is a severe complication of diabetes and the leading cause of blindness among working adults worldwide [1]. The main pathogenic features of PDR are preretinal neovascularization and the formation of fibrovascular membranes at the vitreoretinal interface. The presence of fibrovascular tissue often results in severe visual impairment due to vitreous hemorrhages and/or tractional retinal detachment [3]. Retinal neovascularization has been considered the main characteristic of PDR, the fibrogenic process that occurs after new vessels are formed www.impactjournals.com/oncotarget results in a traction force and, eventually, retinal detachment, suggesting that PDR is a fibrotic disease as well [4]. Müller cells express and secrete growth factors and cytokines that lead to retinal neuron and capillary cell dysfunction [5]. Müller cells can exhibit characteristics of fibroblast cells and can generate tractional force in response to cytokines [6, 9]
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