机构：[1]Department of Ophthalmology of Shanghai Tenth People’s Hospital and Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China[2]Tongji University School of Life Sciences and Technology, Shanghai, China[3]Department of Regenerative Medicine and Stem Cell Research Center, Tongji University School of Medicine, Shanghai, China[4]Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China[5]The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States[6]Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States[7]Institute for Nutritional Sciences, Tongji University School of Medicine, Shanghai, China
PURPOSE. Retinal neuronal cell dysfunction and even cell death are associated with increased excitotoxic glutamate (Glu) level in the retina. Our aim was to study a causative mechanism of Glu on retinal cell death and explore the neuroprotective role of erythropoietin (EPO) against Glu neurotoxicity in the diabetic retina. METHODS. Male Sprague-Dawley (SD) rats and R28 cell line were employed in this study. Diabetes was induced with intraperitoneal injection of streptozotocin (STZ) in SD rats. Two weeks after diabetes onset, the intravitreal injection was performed; 4 days later, the retinas were harvested for testing. R28 cells were treated with Glu, Glu+EPO, or Glu+EPO+soluble EPO receptor (sEPOR), respectively, for 24 hours, and then the cells were collected for the following studies. Glutamate level in the retina was measured with a glutamate assay kit. Cell death was determined with TUNEL staining. The changes in glutamine synthetase (GS), glutamate-aspartate transporter (GLAST), ionotropic glutamate receptors (iGluRs), apoptosis-inducing factor (AIF), and poly(ADP-ribose) (PAR) polymer were studied with RT-PCR, Western blot, and immunofluorescence. RESULTS. In 2-week diabetic rat retinas, Glu concentration was approximately 1.21-fold that in normal control. TUNEL staining demonstrated that retinal cell death was increased. Retinal GS and GLAST expressions were decreased, while the iGluRs, for example, KA1 and NR1, and PAR polymer expression was increased. In R28 cells, 24 hours after Glu (10 mM) treatment, the cell viability was decreased by 52.7%; KA1, NR1, PAR polymer, and nuclear AIF all increased in expression. The above conditions could be largely reversed by EPO both in vivo and in vitro. The protective effect of EPO was abolished by sEPOR. CONCLUSIONS. Erythropoietin showed a neuroprotective function against Glu-mediated neurotoxicity both in diabetic rat retina and in Glu-treated R28 cells. The neuroprotective mechanisms were largely through maintaining the normal expression of glutamate-glutamine cycle-related proteins and inhibiting AIF translocation and PAR polymer formation.
基金：
the National Key Basic
Research Program of China (2011CB965102, 2012CBA01308, and
2013CB967501), National Natural Science Foundation of China
(31171419, 81200693, and 81000383), National High Technology
Research and Development Program of China (2012AA020906),
International Collaboration Fund (2011DFB30010), Research Fund
for the Doctoral Program of Higher Education of China
(20100072120051), Science and Technology Commission of
Shanghai (11DZ1920904), the Fundamental Research Funds for
the Central Universities (2009KJ109), Program of Tongji University
School of Medicine (2010QH04 and 2010YF02), and Unrestricted
Research Fund from the Clear Vision Foundation, Philadelphia,
United States.
第一作者机构：[1]Department of Ophthalmology of Shanghai Tenth People’s Hospital and Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China[2]Tongji University School of Life Sciences and Technology, Shanghai, China[3]Department of Regenerative Medicine and Stem Cell Research Center, Tongji University School of Medicine, Shanghai, China
通讯作者：
通讯机构：[*1]Department of Ophthalmology of Shanghai Tenth People’s Hospital and Tongji Eye Institute, Tongji University School of Medicine, 1239 Siping Road, Medical School Building, Room 521, Shanghai 200092, China[*2]Department of Ophthalmology of Shanghai Tenth People’s Hospital, Tongji Eye Institute, and Department of Regenerative Medicine, Tongji University School of Medicine, 1239 Siping Road, Medical School Building, Room 708, Shanghai 200092, China[*3]Department of Ophthalmology of Shanghai Tenth People’s Hospital, and Tongji Eye Institute, Tongji University School of Medicine, 1239 Siping Road, Medical School Building, Room 708, Shanghai 200092, China
推荐引用方式(GB/T 7714)：
Limin Gu ,Hua Xu ,Fang Wang ,et al.Erythropoietin Exerts a Neuroprotective Function Against Glutamate Neurotoxicity in Experimental Diabetic Retina[J].INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE.2014,55(12):8208-22.doi:10.1167/iovs.14-14435.
APA：
Limin Gu,,Hua Xu,,Fang Wang,,Guoxu Xu,,Debasish Sinha,...&GuoTong Xu.(2014).Erythropoietin Exerts a Neuroprotective Function Against Glutamate Neurotoxicity in Experimental Diabetic Retina.INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE,55,(12)
MLA：
Limin Gu,,et al."Erythropoietin Exerts a Neuroprotective Function Against Glutamate Neurotoxicity in Experimental Diabetic Retina".INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 55..12(2014):8208-22
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