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W.-K. Ju, K.-Y. Kim, J. D. Lindsey, M. H. Ellisman, R. N. Weinreb; Elevated Intraocular Pressure Increases Cycline B1/Drp1 Phosphorylation-Mediated Retinal Ganglion Cell Death in Glaucomatous Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6123.
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Increased dynamin-related protein 1 (Drp1) expression triggers excessive mitochondrial fission and induces apoptotic cell death. The goal of this study is to determine whether elevated intraocular pressure (IOP) alters Drp1 protein expression and cyclin B1/Drp1 phospohorylation at Ser616 in the retina of a mouse model of glaucoma
IOP in the eye of glaucomatous DBA/2J mice was measured. The cellular distribution of Drp1 and phospho-Drp1 (Ser616) protein was assessed by immunohistochemistry or Western blot. Apoptotic cell death was assessed by TUNEL staining. Bcl-2 and Bax mRNA were measured by quantitative PCR.
Drp1, cyclin B1, and phospho-Drp1 (Ser616) protein were significantly increased by 1.29 ± 0.04-fold, 1.57 ± 0.15-fold, and 1.39 ± 0.11-fold (n = 4 retinas per pool, P < 0.05) in the retinas of 9 month-old glaucomatous DBA/2J mice. Immunohistochemistry analysis showed that phospho-Drp1 (Ser616) immunoreactivity was increased in the GCL of 9 month-old glaucomatous DBA/2J mice. Quantitative PCR analysis showed that elevated IOP significantly increased Bax mRNA expression in the retinas of glaucomatous DBA/2J mice. However, Bcl-2 mRNA expression was not changed. Finally, apoptotic cell death was increased in the GCL of glaucomatous DBA/2J mice.
These results provide the first evidence linking elevated IOP-mediated RGC death to increased Drp1 and cyclinB1/Drp1 phosphorylation at Ser616 in glaucomatous mouse model. Based on this observation, we propose that increased Drp1 and cyclinB1/Drp1 phosphorylation at Ser616 may contribute to a distinct mitochondria-mediated RGC death in glaucomatous retina.
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