EPO reduces reactive gliosis and stimulates neurotrophin expression in Muller cells

Hu, Liu; Luo, Yan; Zhang, Jingfa; Lei, Xia; Shen, Jianfeng; Wu, Yalan; Qin, Mei; Ünver, Yaprak Banu; Zhong, Yong; Xu, Guo; Li, Weiye

doi:10.2741/e355

Cited by 15 publications

(2 citation statements)

References 47 publications

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“…EPO was previously found to exert protective effects in diabetic retinopathy [19][20][21][22]. In our previous study we demonstrated that EPO preserved the integrity of the iBRB and attenuated vascular leakage through inhibition of hypoxia-inducible factor-1α/VEGF signalling [19].…”

Section: Discussionmentioning

confidence: 86%

“…Erythropoietin (EPO), besides stimulating erythrocyte production, has multiple functions, including neurotrophic activity in ischaemic damage and stroke, Parkinson's disease and retinal degeneration [16]. We previously evaluated the efficacy, pharmacokinetics, toxicity and mechanism of action of EPO in experimental diabetic retinopathy [17][18][19] and found that it has protective effects in retinal neurons [20], microvascular endothelium [19], retinal pigment epithelium (RPE) [21] and Müller cells [22].…”

Section: Introductionmentioning

confidence: 99%

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Erythropoietin protects the inner blood–retinal barrier by inhibiting microglia phagocytosis via Src/Akt/cofilin signalling in experimental diabetic retinopathy

et al. 2020

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Aims/hypothesis Microglial activation in diabetic retinopathy and the protective effect of erythropoietin (EPO) have been extensively studied. However, the regulation of microglia in the retina and its relationship to inner blood-retinal barrier (iBRB) maintenance have not been fully characterised. In this study, we investigated the role of microglia in iBRB breakdown in diabetic retinopathy and the protective effects of EPO in this context. Methods Male Sprague Dawley rats were injected intraperitoneally with streptozotocin (STZ) to establish the experimental model of diabetes. At 2 h after STZ injection, the right and left eyes were injected intravitreally with EPO (16 mU/eye, 2 μl) and an equivalent volume of normal saline (NaCl 154 mmol/l), respectively. The rats were killed at 2 or 8 weeks after diabetes onset. Microglia activation was detected by ionised calcium binding adaptor molecule (IBA)-1 immunolabelling. Leakage of the iBRB was evaluated by albumin staining and FITC-dextran permeability assay. BV 2 cells and primary rat microglia under hypoxic conditions were used to model microglial activation in diabetic retinopathy. Phagocytosis was examined by confocal microscopy in flat-mounted retina preparations and in microglia and endothelial cell cocultures. Protein levels of IBA-1, CD11b, complement component 1r (C1r), and Src/Akt/cofilin signalling pathway components were assessed by western blotting. Results In diabetic rat retinas, phagocytosis of endothelial cells by activated microglia was observed at 8 weeks, resulting in an increased number of acellular capillaries (increased by 426.5%) and albumin leakage. Under hypoxic conditions, activated microglia transmigrated to the opposite membrane of the transwell, where they disrupted the endothelial cell monolayer by engulfing endothelial cells. The activation and phagocytic activity of microglia was blocked by intravitreal injection of EPO. In vitro, IBA-1, CD11b and C1r protein levels were increased by 50.9%, 170.0% and 135.5%, respectively, by hypoxia, whereas Jingfa Zhang and Guo-Tong Xu contributed equally to this study.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Erythropoietin protects the inner blood–retinal barrier by inhibiting microglia phagocytosis via Src/Akt/cofilin signalling in experimental diabetic retinopathy

et al. 2020

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Epo inhibits the fibrosis and migration of Müller glial cells induced by TGF-β and high glucose

Luo

et al. 2016

Graefes Arch Clin Exp Ophthalmol

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

Zhang

et al. 2018

Eye

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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.

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EPO reduces reactive gliosis and stimulates neurotrophin expression in Muller cells

Cited by 15 publications

References 47 publications

Erythropoietin protects the inner blood–retinal barrier by inhibiting microglia phagocytosis via Src/Akt/cofilin signalling in experimental diabetic retinopathy

Erythropoietin protects the inner blood–retinal barrier by inhibiting microglia phagocytosis via Src/Akt/cofilin signalling in experimental diabetic retinopathy

Epo inhibits the fibrosis and migration of Müller glial cells induced by TGF-β and high glucose

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

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