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Changes in Gene Expression in Experimental Glaucoma and Optic Nerve Transection: The Equilibrium between Protective and Detrimental Mechanisms

²From the Glaucoma Service and ³Dana Center for Preventive Ophthalmology at the Wilmer Eye Institute, the ¹Departments of Ophthalmology, ⁴Molecular Biology and Genetics, and ⁵Neuroscience, at the Guerrieri Family Center for Genetic Engineering and Molecular Ophthalmology, and the ⁶Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

PURPOSE. The authors studied retinal gene expression changes in rats after experimental intraocular pressure elevation and optic nerve transection to elucidate molecular mechanisms of retinal ganglion cell (RGC) death.

METHODS. Translimbal laser photocoagulation was used to induce unilateral IOP elevation in 41 albino Wistar rats. In 38 additional animals, unilateral transection of the optic nerve was performed. Retinas were harvested 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 8 weeks after each treatment, and total RNA was isolated. Pooled RNA from each time point was analyzed with rat genome arrays. Array results were confirmed by real-time PCR, and localization studies were performed using in situ hybridization for select genes.

RESULTS. Genes that were upregulated in glaucoma, but not after transection, included Cyclin D2, Stat1, Stat3, c-Fos, Junb, Anxa1, Anxa 3, and CCAAT/enhancer binding protein (Cebp-delta). In glaucoma and transection models, the upregulation of c-Jun, Activating transcription factor 3, Heat shock protein 27, and Timp1 were observed. Comparisons among microarray databases were performed between our data and reports of retinal and optic nerve injury models in mice, rats, and monkeys.

CONCLUSIONS. Gene expression changes specific to experimental glaucoma injury were identified. The present analysis supports the importance of neuroinflammation and the participation of the tumor necrosis factor alpha signaling pathway in glaucoma injury. The alterations observed include processes that are both protective of and detrimental to the survival of RGCs.

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