Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure  

作　　者：Xue YANG Xiaowei YU Zhenni ZHAO Yuqing HE Jiamin ZHANG Xiaoqian SU Nannan SUN Zhigang FAN 

机构地区：[1]State Key Laboratory of Ophthalmology,Department of Glaucoma,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangzhou 510060,China [2]Tongren Eye Center,Beijing Tongren Hospital,Capital Medical School,Beijing 100730,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2021年第9期746-756,共11页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the Guangzhou Science and Technology Plan Project(Nos.201803040020,201903010065;202102021099);the Guangdong Natural Science Foundation(No.2020A151501168);the Research Funds of the State Key Laboratory of Ophthalmology(No.PT1001022),China。

摘　　要：Clinically,a large proportion of glaucoma patients undergo repeated intraocular pressure(IOP)spike(Spike IOP)attacks during their sleep,which may facilitate retinopathy.In this study,we established a mouse model of repeated transient Spike IOP to investigate the direct damage to the retina following Spike IOP attacks,and elucidated the underlying molecular mechanism.We analyzed the changes in the number of retinal ganglion cells(RGCs)via immunofluorescence.Thereafter,we detected retinal cell apoptosis via terminal deoxynucleotidyl transferase deoxyuridine triphosphate(d UTP)nick-end labeling(TUNEL)staining,and performed RNA sequencing(RNA-seq)to reveal the underlying molecular mechanism.Finally,we validated the expression of key molecules in the endoplasmic reticulum(ER)stress pathway using quantitative real-time polymerase chain reaction(q RT-PCR)and western blot analysis.Results revealed a time-dependent RGC loss in Spike IOP,evidenced by a reduction in the number of Brn3 a-positive RGCs in experimental eyes following a 7-d continuous treatment with Spike IOP.In addition,TUNEL staining indicated that apoptosis of retinal cells started in the outer nuclear layer(ONL),and then spread to the ganglion cell layer(GCL)with time.RNA-seq analysis revealed that ER stress might be involved in Spike IOP-induced retinal injury.This result was corroborated by western blot,which revealed upregulation of ER stress-related proteins including binding immunoglobulin protein/glucose-regulated protein 78(Bi P/GRP78),phosphorylated inositolrequiring enzyme 1(p-IRE1),unspliced X-box-binding protein 1(XBP1-u),spliced X-box-binding protein 1(XBP1-s),phosphorylated c-Jun N-terminal kinase(p-JNK),C/EBP-homologous protein(CHOP),and B-cell lymphoma 2(Bcl-2)-associated X protein(Bax).These findings indicate that repeated IOP transients are detrimental to the retina,while ER stress plays an important role in retinal cell apoptosis in this situation.Notably,repeated Spike IOP among glaucoma patients is a crucial factor for progressive retino

关 键 词：Endoplasmic reticulum(ER)stress Intraocular pressure spike(Spike IOP) Retinal injury Neuron apoptosis GLAUCOMA 

分 类 号：R774.1[医药卫生—眼科]