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Effect of an Inducer of BiP, a Molecular Chaperone, on Endoplasmic Reticulum (ER) Stress-Induced Retinal Cell Death

¹From the Departments of Biofunctional Evaluation, Molecular Pharmacology and ²Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, Japan; ³Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan; ⁴Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; and ⁵Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.

PURPOSE. The effect of a preferential inducer of 78 kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein (BiP; BiP inducer X, BIX) against tunicamycin-induced cell death in RGC-5 (a rat ganglion cell line), and also against tunicamycin- or N-methyl-D-aspartate (NMDA)-induced retinal damage in mice was evaluated.

METHODS. In vitro, BiP mRNA was measured after BIX treatment using semi-quantitative RT-PCR or real-time PCR. The effect of BIX on tunicamycin (at 2 µg/mL)-induced damage was evaluated by measuring the cell-death rate and CHOP protein expression. In vivo, BiP protein induction was examined by immunostaining. The retinal cell damage induced by tunicamycin (1 µg) or NMDA (40 nmol) was assessed by examining ganglion cell layer (GCL) cell loss, terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, and CHOP protein expression.

RESULTS. In vitro, BIX preferentially induced BiP mRNA expression both time- and concentration-dependently in RGC-5 cells. BIX (1 and 5 µM) significantly reduced tunicamycin-induced cell death, and BIX (5 µM) significantly reduced tunicamycin-induced CHOP protein expression. In vivo, intravitreal injection of BIX (5 nmol) significantly induced BiP protein expression in the mouse retina. Co-administration of BIX (5 nmol) significantly reduced both the retinal cell death and the CHOP protein expression in GCL induced by intravitreal injection of tunicamycin or NMDA.

CONCLUSIONS. These findings suggest that this BiP inducer may have the potential to be a therapeutic agent for endoplasmic reticulum (ER) stress–induced retinal diseases.