Abstract
Glucose is one of the most important metabolic substrates of the retina, and glycaemic imbalances can lead to serious side effects, including retinopathy. We previously showed that hypoglycaemia induces retinal cell death in mice, as well as the implication of glutathione (GSH) in this process. This study aimed to analyse the role of low glucose-induced decrease in GSH levels in endoplasmic reticulum (ER) stress. We cultured 661W photoreceptor-like cells under various glucose conditions and analysed ER stress markers at the mRNA and protein levels. We used the ERAI (“ER stress-activated indicator”) mouse model to test ER stress in both ex vivo, on retinal explants, or in vivo, in mice subjected to hypoglycaemia. Moreover, we used buthionine sulfoximine (BSO) and glutamate cysteine ligase (Gclm)-KO mice as models of low GSH to test its effects on ER stress. We show that the unfolded protein response (UPR) is triggered in 661W cells and in ERAI mice under hypoglycaemic conditions. Low GSH levels promote cell death, but have no impact on ER stress. We concluded that low glucose levels induce ER stress independently of GSH levels. Inhibition of ER stress could prevent neurodegeneration, which seems to be an early event in the pathogenesis of diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is the leading cause of vision impairment in working-age adults [1]
Since unfolded protein response (UPR) is triggered by glucose deprivation and photoreceptors have the highest demand for energy among retinal cells, we investigated whether UPR is triggered in 661W photoreceptor cells under low-glucose conditions
We observed a significant increase in the expression of Bip (5-fold) and Chop (15-fold)
Summary
Diabetic retinopathy (DR) is the leading cause of vision impairment in working-age adults [1]. DR has been identified as a vascular disease caused by the increased production of reactive oxygen species (ROS) in pericytes and capillary endothelial cells due to chronic hyperglycaemia [3,4]. An increasing body of evidence suggests that neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, which could precede the development of microvascular abnormalities [5,6]. Neural apoptosis and reactive gliosis, the hallmarks of retinal degeneration, have already been reported in diabetic patients without microcirculatory abnormalities [7,8]. ROS production and oxidative stress have been shown to be central events in the development of DR [9,10]
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