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Abstract
In the early stages of diabetic retinopathy (DR), subtle biochemical and functional alterations occur in Müller cells, which are one of the components of the blood–retinal barrier (BRB). Müller cells are the principal glia of the retina and have shown a strong involvement in the maintenance of homeostasis and the development of retinal tissue. Their functional abnormalities and eventual loss have been correlated with a decrease in the tight junctions between endothelial cells and a consequent breakdown of the BRB, leading to the development of DR. We demonstrated that the endothelium reticulum (ER) triggers Müller cell death and that nuclear accumulation of glyceraldehyde 3-phosphate dehydrogenase is closely associated with ER-induced Müller cell death. In addition, induction of ER stress in Müller cells increased vascular endothelial growth factor expression but decreased pigment-epithelium-derived factor (PEDF) expression in Müller cells. We found that nobiletin, a polymethoxylated flavone from citrus explants, exerts protective action against ER-stress-induced Müller cell death. In addition, nobiletin was found to augment PEDF expression in Müller cells, which may lead to the protection of BRB integrity. These results suggest that nobiletin can be an attractive candidate for the protection of the BRB from breakdown in DR.
Highlights
Müller cells are one of glial cells in the retina and the signature cells to spread through the retina and are in contact with retinal vessels and neurons [1,2]
endothelium reticulum (ER) stress can be chemically induced by tunicamycin (Tm) or thapsigargin (Tg); we examined the actions of ER stress inducers Tm and Tg on Müller cell survival
A polymethoxylated flavone from citrus explants, has inhibitory potential in ER-stress-induced Müller cell death
Summary
Müller cells are one of glial cells in the retina and the signature cells to spread through the retina and are in contact with retinal vessels and neurons [1,2]. Müller cells possess critical functions in the modulation of blood flow and the maintenance of the blood–retinal barrier (BRB) [3,4,5]. There are several reports that Müller cells induce blood–retinal barrier integrity in retinal endothelial cells [2,6,7]. Several reports suggest that Müller cells are involved in BRB properties by producing factors such as pigmentepithelium-derived factor (PEDF) and thrombospondin-1, which are anti-angiogenic and strengthen the endothelial barrier [4,9,10]. The barrier function is impaired by vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) derived from Müller cells [11] as MMPs lead to the degradation of the tight junction protein occuldin [12]. The hypoxic condition is known as one of the stimuli leading to the induction of these pathogenetic factors [14]
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