Abstract
Retinal ischemia/reperfusion (I/R) injury is an important cause of visual impairment. However, questions remain on the overall I/R mechanisms responsible for progressive damage to the retina. In this study, we used a mouse model of I/R and characterized the pathogenesis by analyzing temporal changes of retinal morphology and function associated with changes in retinal gene expression. Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. At various time points post I/R, retinal changes were monitored by histological assessment with H&E staining and by SD-OCT scanning. Retinal function was also measured by scotopic ERG. Temporal changes in retinal gene expression were analyzed using cDNA microarrays and real-time RT-PCR. In addition, retinal ganglion cells and gliosis were observed by immunohistochemistry. H&E staining and SD-OCT scanning showed an initial increase followed by a significant reduction of retinal thickness in I/R eyes accompanied with cell loss compared to contralateral control eyes. The greatest reduction in thickness was in the inner plexiform layer (IPL) and inner nuclear layer (INL). Retinal detachment was observed at days 3 and 7 post- I/R injury. Scotopic ERG a- and b-wave amplitudes and implicit times were significantly impaired in I/R eyes compared to contralateral control eyes. Microarray data showed temporal changes in gene expression involving various gene clusters such as molecular chaperones and inflammation. Furthermore, immunohistochemical staining confirmed Müller cell gliosis in the damaged retinas. The time-dependent changes in retinal morphology were significantly associated with functional impairment and altered retinal gene expression. We demonstrated that I/R-mediated morphological changes the retina closely associated with functional impairment as well as temporal changes in retinal gene expression. Our findings will provide further understanding of molecular pathogenesis associated with ischemic injury to the retina.
Highlights
Retinal ischemia, often referred as “stroke of retina”, is an important cause of visual impairment in retinal vascular occlusion, diabetic retinopathy, glaucoma, and ocular trauma [1,2,3,4,5]
I/R injury induced progressive degeneration of inner retinal layers (IRLs) and decreased cell numbers in the retinal ganglion cell layer Histological measurements of H&E stained retinas showed that I/R injury significantly (p < 0.05) increased retinal thickness of the inner retinal layers (IRLs), inner plexiform layer (IPL) and inner nuclear layer (INL), at day 3 followed by progressive decreases in thickness after 14 days (Figure 2A and 2B)
Layer thickness was decreased in only IRLs, IPL and INL, but not in the outer nuclear layer (ONL) (Figure 2B)
Summary
Often referred as “stroke of retina”, is an important cause of visual impairment in retinal vascular occlusion, diabetic retinopathy, glaucoma, and ocular trauma [1,2,3,4,5]. It is caused by a reduction of the retinal blood supply that decreases the delivery of oxygen and other nutrients to various retinal layers. After a specified period of time, the cannula is removed allowing restoration of retinal blood flow This model has been used for the investigation of ischemiaderived ocular pathologies such as glaucoma and diabetic retinopathy [13,14]. This model currently is the most widely used method to study ocular diseases related to retinal ischemia
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