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M. Awai, M. Awai, T. Koga, Y. Inomata, A. Hirata, H. Tanihara; NMDA–induced retinal injury is mediated by endoplasmic reticulum stress pathway, involving CHOP. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):722.
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Purpose:Endoplasmic reticulum (ER) has several important functions involving glycosylation, formation of disulfide bonds, folding and assembly of newly–synthesized secretory proteins. ER also serves as a cellular Ca2+ store. Perturbation of ER functions can induce cellular damages and result in cell death. C/EBP homologues protein (CHOP) is a transcriptional factor induced under ER stress condition, and mediated apoptosis. We investigate the relationship of N–methyl–D–aspartate (NMDA)–induced retinal damage and ER stress pathway, involving CHOP. Methods:Eight weeks old male C57B6 mice were treated with intravitreous injection of 5 nmol NMDA, and the eyes were enucleated at 2, 6, 12 and 24 h. Apoptotic cells were assessed by TUNEL method. Expression of CHOP protein was estimated by immunohistochemical technique. In the eyes of wild type and CHOP (–/–) mice treated with 1, 2, 5, 10 nmol NMDA, respectively, TUNEL positive cells in retina were counted at 24 h and molphometric analyses were performed at 7 day. Results:TUNEL positive cells were undetectable at 2 h, detected in retinal ganglion cell layer and inner nuclear layer at 6 h, and gradually increased up to 24 h. Immunoreactivities of CHOP protein were also detected in retinal ganglion cell layer and inner nuclear layer. TUNEL method revealed that retinal cell death was significantly suppressed in CHOP (–/–) mice treated with 2 or 5 nmol NMDA, compared with wild type mice. Furthermore, retinal injury was significantly reduced in CHOP (–/–) mice treated with 2 nmol NMDA by molphometric analyses such as retinal ganglion cell counts and thickness of inner nuclear layer. Conclusions:ER stress gene, CHOP, is induced in NMDA treated mouse retina and CHOP (–/–) mice are resistant to NMDA induced retinal damage. These results suggest that ER stress pathway, especially to CHOP gene, play an important role in NMDA induced retinal cell death.
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