机构：[1]Department of Ophthalmology of Shanghai Tenth People’s Hospital, Tongji Eye Institute, Tongji University School of Medicine (TUSM), Shanghai, China[2]Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China[3]Department of Regenerative Medicine and Stem Cell Research Center, TUSM, Shanghai, China
PURPOSE. Zinc transporter 8 (ZnT8) was downregulated in hypoxic retina, which could be rescued by hypoxia-inducible factor-1 alpha (HIF-1 alpha) inhibition. Erythropoietin (EPO) protects retinal cells in diabetic rats through inhibiting HIF-1 alpha as one of its mechanisms. We hence tried to explore the effect of EPO in regulating ZnT8 and protecting retinal cells in diabetic rats and possible mechanisms. METHODS. Diabetes was induced in Sprague-Dawley rats. Intravitreal injection of EPO was performed 1 month after diabetes onset. The CoCl2-treated rat Muller cell line (rMC-1) was cotreated with EPO, soluble EPO receptor (sEPOR), digoxin, or U0126. Cell viability, cell death, and intracellular zinc level were examined. The expression of ZnT8, HIF-1 alpha, AKT, and ERK was studied. RESULTS. In diabetic rat retinas, EPO significantly decreased HIF-1 alpha expression and increased ZnT8 expression. In CoCl2-treated rMC-1 cells, EPO increased cell viability and decreased intracellular zinc. Erythropoietin or digoxin could activate ERK pathway, downregulate HIF-1 alpha, and upregulate ZnT8. The effect of EPO was abolished by sEPOR and U0126. Transient knockdown of ZnT8 increased intracellular zinc level, but not to a degree that would decrease cell viability or cause cell death. CONCLUSIONS. In diabetic retinas, EPO maintains zinc homeostasis through activating the ERK pathway and downregulating HIF-1 alpha, and thus upregulating ZnT8 expression. This work proposed a possible new protective mechanism for EPO in, and indicated a potential target for, the treatment of diabetic retinopathy.
基金：
Supported by the Key State Basic Research Development Program
of China (2012CBA01308 and 2013CB967501), National Natural
Science Foundation of China (81570852 and 31171419), National
High Technology Research and Development Program of China
(2012AA020906), and Shanghai Pujiang Program (15PJ1408700).
第一作者机构：[1]Department of Ophthalmology of Shanghai Tenth People’s Hospital, Tongji Eye Institute, Tongji University School of Medicine (TUSM), Shanghai, China[2]Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, 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, 301 Middle Yanchang Road, Building 1, 15th Floor, Director’s Office, Shanghai 200072, China[*2]Department of Ophthalmology of Shanghai Tenth People’s Hospital, and Tongji Eye Institute, Tongji University School of Medicine, 301 Middle Yanchang Road, Building 1, Room 307, Shanghai 200072, China
推荐引用方式(GB/T 7714)：
Guoxu Xu,Daohuan Kang,Chaoyang Zhang,et al.Erythropoietin Protects Retinal Cells in Diabetic Rats Through Upregulating ZnT8 via Activating ERK Pathway and Inhibiting HIF-1 alpha Expression[J].INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE.2015,56(13):8166-78.doi:10.1167/iovs.15-18093.
APA：
Guoxu Xu,Daohuan Kang,Chaoyang Zhang,Hui Lou,Chen Sun...&Fang Wang.(2015).Erythropoietin Protects Retinal Cells in Diabetic Rats Through Upregulating ZnT8 via Activating ERK Pathway and Inhibiting HIF-1 alpha Expression.INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE,56,(13)
MLA：
Guoxu Xu,et al."Erythropoietin Protects Retinal Cells in Diabetic Rats Through Upregulating ZnT8 via Activating ERK Pathway and Inhibiting HIF-1 alpha Expression".INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 56..13(2015):8166-78
医学