Retinal ganglion cell death induced by endoplasmic reticulum stress in a chronic glaucoma model.
This study investigated whether endoplasmic reticulum (ER) stress induced retinal ganglion cell (RGC) death in chronic ocular hypertension, one of the RGC death mechanisms, using an experimental glaucoma rat model. Glaucoma was induced in adult male Sprague-Dawley rats by cauterizing three episcleral veins. The intraocular pressure (IOP) remained elevated in the cauterized eyes for the 8-week experiment, whereas it was not elevated in the contralateral control eyes. The average number of RGCs decreased significantly, and TUNEL-positive cells were detected in the ganglion cell layer. In western blotting, Bip, the phosphorylated form of PKR (p-PERK), and C/EBP-homologous protein (CHOP) were significantly expressed at 1 or 2 weeks, and this persisted throughout the 8-week experiment. Phosphorylated eukaryotic initiation factor 2 (p-eIF2alpha) began to increase at 1 week, was sustained through 4 weeks, and decreased slightly at 8 weeks. In cauterized eyes, strong p-PERK and CHOP immunoreactivity was observed in ganglion cells after 8 weeks of IOP elevation. Taken together, in the experimental chronic glaucoma model, ER stress is involved in RGC death, and the PERK-p-eIF2alpha-CHOP pathway plays a role in the RGC apoptosis associated with ER stress. This might be a good therapeutic target to protect RGCs from ER stress injury in glaucoma.
Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
Sang Hee
SH
Doh
Jie Hyun
JH
Kim
Kyung Min
KM
Lee
Hae Young
HY
Park
Chan Kee
CK
Park
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D016923:Cell Death; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005901:Glaucoma / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007429:Intraocular Pressure; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D013312:Stress, Physiological; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D009842:Oligopeptides; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C539791:Bax-inhibiting peptide, BIP; C497250:Ddit3 protein, mouse