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K. Hashimoto, M. Hernandez; Expression of c–fos, c–jun and egr–2 in retinas and optic nerve heads of mice with unilateral ocular hypertension. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2162.
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Purpose: c–fos, c–jun and egr–2 were identified as intermediate early gene (IEG) products in human ONH astrocytes exposed to elevated hydrostatic pressure. Here we determined whether these IEG products are expressed in a mouse model of ocular hypertension. Methods:Twenty C57BL/6 mice with unilateral ocular hypertension were used. To raise intraocular pressure (IOP), three episcleral veins were ligated; the intact contralateral eye served as normal control. IOP was measured using a microneedle method at days 0, 3, 7, 15, 30. After sacrifice, the optic nerves were dissected, embedded in Epon and used for axon counting. Sagittal sections of the retina and optic nerves were embedded in paraffin and stained by immunofluorescence with antibodies against GFAP for astrocytes, Thy1.2 for retinal ganglion cells (RGCs), c–fos, c–jun, egr2 and the nuclear stain, DAPI. Results: The mean corrected IOP in untreated eyes was 14.8+1.2 mmHg (n=20). The IOP of treated eyes increased at 3 days to 25.1+1.1 (n=4); at 7 days to 24.9+1.7 (n=4); at 15 days to 24.3+0.6 (n=4); and at 30 days to 23.1+1.9 mmHg (n=4). The average number of axons, the mean axon density and the mean optic nerve area of eyes with elevated IOP decreased after 7 days (p<0.05) and continued to decrease after 15 (p<0.01) and 30 days (p<0.006). In eyes with normal IOP, c–fos and c–jun were expressed in the cytoplasm of RGCs and ONH astrocytes. Egr2 was not expressed in normal control eyes in the retina or ONH. After IOP elevation for 3 days, nuclear egr2 was present in a few RGCs. At 7 days, nuclear egr2 in RGCs increased and at 15 days, egr2 was markedly present in many RGC nuclei. At 15 days, c–jun began appearing in the nuclei of RGCs; however, c–fos remained cytoplasmic. At 30 days, many RGCs exhibited nuclear egr2 and c–fos; whereas, nuclear c–jun declined. At 7, 15 and 30 days, nuclear egr2 was strongly expressed in ONH astrocytes. Nuclear c–fos was detectable in most ONH astrocytes at 7 and 15 days but declined at 30 days. Nuclear c–jun was present in ONH astrocytes at 3, 7, 15, and 30 days. Conclusions: Ligation of 3 episcleral veins can elevate IOP in the mouse eye to 25 mmHg for at least 30 days. Furthermore, c–fos, c–jun and egr–2, which are IEG products responsive to mechanical stress and pressure, appear to steadily increase in the astrocytes and RGCs of eyes with elevated IOP. Nuclear localization of egr2, c–fos and c–jun in ONH astrocytes in ocular hypertension occurred earlier than in RGCs, suggesting that ONH astrocytes may be the first cells to sense IOP elevation. The combined activation of these transcription factors may regulate transcriptional responses to IOP.
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