GSH-Independent Induction of ER Stress during Hypoglycaemia in the Retinal Cells of Mice

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.

Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

“…Metabolic changes can facilitate DR and ER stress in DR retinas and can provide metabolism sensors for glucose fluctuations (hypoglycemia and elevated glucose), O-GlcNAcylation, low-density lipoprotein, copper, and advanced glycation end products (AGEs). [184][185][186] All three UPR pathways are activated in the DR process. [187][188][189][190][191][192][193][194] Function of ER stress in BRB breakdown in DR. BRB can be divided into inner and outer components, with the inner BRB being formed by tight junctions between neighboring retinal capillary endothelial cells and the outer barrier by tight junctions between retinal pigment epithelium (RPE) cells.…”

State-of-the-Art Research on Diabetic Retinopathy

“…As is generally the case in science, basic research is the backbone for nourishing innovation and usually provides us with a myriad of proof of concepts to be tested in the clinical setting. In this Special Issue, Fresia et al [12] presented an elegant experimental work showing the deleterious effects of hypoglycemia on the neuroretina and the underlying mechanisms. This is very interesting because the published information regarding the effects of hypoglycemia on the neuroretina is scarce and cannot be extrapolated to the abundant reports on this issue that exist on the brain.…”