Time-dependent changes in hypoxia- and gliosis-related factors in experimental diabetic retinopathy

Abstract

Diabetes causes various biochemical changes in the retina; long-term changes in the factors associated with hypoxia and gliosis have rarely been reported. The present study was conducted to explore the changes in these factors in a time-dependent manner in experimental diabetic retinopathy (DR). Diabetes was induced in Sprague–Dawley rats by intraperitoneal injection of streptozotocin. The expression of the following factors was examined using immunofluorescence and western blot analysis at 0.5, 1, 2, 4 and 6 months after diabetes onset: hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin (EPO), erythropoietin receptor (EPOR), glial fibrillary acidic protein (GFAP), vimentin, glutamate-aspartate transporter (GLAST) and glutamine synthase (GS). The expression of factors such as HIF-1alpha, VEGF, EPO, EPOR, GFAP and vimentin, was up-regulated with the progression of diabetes in the diabetic rat retinas compared to the expression in normal control retinas, whereas the expression of GS and GLAST was down-regulated. Changes in EPO and EPOR appeared 2 weeks after diabetes onset. HIF-1alpha, VEGF and GFAP started to increase at 1 month and vimentin at 4 months after diabetes onset. GS and GLAST started to decrease at 1 month after diabetes onset. The expression of these factors, which are involved in the processes of hypoxia and gliosis, varied at different stages of DR. The time-course change may be helpful in the evaluation of the progression of DR, and it may indicate the optimal intervention time points for DR.

VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions

“…41 Similarly, oxidative stress and hypoxia are implicated in the development of diabetic retinopathy. 47,48 In this condition, an impaired Müller cell GS and dysregulation K + and water transportation have been reported; ultimately, this process may lead to glutamate excitotoxicity, Müller cell swelling, and degeneration of the inner retina. 2,47,48 Diabetic retinopathy also increases the production of neurotrophic factors such as VEGF-A, and was found to be one of the few pathologies that affects Müller cell viability.…”

“…47,48 In this condition, an impaired Müller cell GS and dysregulation K + and water transportation have been reported; ultimately, this process may lead to glutamate excitotoxicity, Müller cell swelling, and degeneration of the inner retina. 2,47,48 Diabetic retinopathy also increases the production of neurotrophic factors such as VEGF-A, and was found to be one of the few pathologies that affects Müller cell viability. 1,2 In this study, VEGF-B production in Müller cells was increased under both oxidative stress and hypoxic conditions.…”

Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

“…Following inherited or acquired retinal pathology, GFAP is expressed also in Muller cells [19,20]. GFAP expression in Muller cells has been widely used as a cellular marker for retinal pathology [21][22][23][24][25]. Hypoxia-inducible factor 1 alpha (HIF-1α) is known to be a key regulator of a tissue's response to hypoxia [26] and plays a role in obesity-induced metabolic syndrome.…”

Synthetic Glucocorticoid-Induced Leucine Zipper Peptide Inhibits Lipopolysaccharide-Induced Ocular Inflammation in Rats

“…Müller cells undergo notable reactive gliosis in response to various pathological stimuli in various central nervous system diseases [36,37]. Gliosis involves an increase in the release of vimentin [38] and a reduction in AQP-4 expression [39]. Müller cells are the predominant type of glial cells in the retina and play an important role in maintaining retinal homeostasis [40,41].…”