Abstract
The degeneration of Müller cells has been recognized to involve in the pathogenesis of diabetic retinopathy. However, the mechanism is not yet clear. This study is to explore the potential role of Cyr61, a secreted signaling protein in extracellular matrix, in inducing human Müller cell degeneration in diabetic retinopathy (DR). Twenty patients with proliferative diabetic retinopathy (PDR) and twelve non-diabetic patients were recruited for this study. Vitreous fluid was collected during vitrectomy surgery for Cyr61 ELISA. Human Müller cell line MIO-M1 were cultured to be subconfluent, and then treated with glucose (0–20 mM) or Cyr61 (0–300 ng/ml). Cyr61 expression induced by increasing concentrations of glucose was evaluated by RT-qPCR and Western blot. Effects of Cyr61 on Müller cells viability, migration and apoptosis were observed by MTT assay, Transwell assay, and TUNEL assay. Vitreous Cyr61 levels were observed to be 8-fold higher in patients with PDR (3576.92±1574.58 pg/mL), compared with non-diabetic controls (436.14±130.69 pg/mL). Interestingly, the active PDR group was significantly higher than the quiescent PDR group (P<0.01). In retinal Müller cells culture, high glucose significantly and dose-dependently elevated Cyr61 expression at both mRNA and protein levels. Cyr61 at high concentrations dose-dependently inhibited the viability and migration of Müller cells. TUNEL assay further revealed that high concentration of Cyr61 significantly promoted the cell apoptosis. In conclusion, these findings demonstrated for the first time that the expression of Cyr61 was elevated by high glucose in Müller cells, and Cyr61 inhibited cell viability and migration while induced apoptosis, suggesting the potential role of Cyr61 in Müller cell degeneration. The elevated Cyr61 levels in vitreous fluid of PDR patients further support its role in diabetic retinopathy (DR).
Highlights
IntroductionIts pathophysiology involves the degeneration of the retinal neurons and dysfunction of the retinal microvasculature, followed by macular edema and neovascularization of the retina
Diabetic retinopathy (DR) is one of the leading causes of visual impairment [1,2]
It was revealed that high glucose significantly elevated Cyr61 expression in Muller cells with dose-dependent and time-dependent manner
Summary
Its pathophysiology involves the degeneration of the retinal neurons and dysfunction of the retinal microvasculature, followed by macular edema and neovascularization of the retina. Less attention has been paid to the degeneration of the Muller cells, which anatomically and physiologically account for additional pathologic mechanisms in diabetic retinopathy [3,4,5]. Muller cells are the primary retinal glial cells, radically spanning within the full thickness of the retina. Muller cells express ion channels, water channels and glutamate transporters that strictly regulate the retinal microenvironment, dysfunction of which leads to macular edema and the toxicity of the retinal neurons [8]. Muller cells could secret several trophic factors, such as glial cell line-derived neurotrophic factor and basic fibroblast growth factor, to protect the photoreceptors [9,10,11]. The degeneration of Muller cells may accelerate the apoptosis of the neurons in pathologic stimulus
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