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S. J. Glass, Y. L. Wang, E. Hernandez, M. E. Fini, M. L. Bajenaru; TGF-β Signaling Pathway and Extracellular Matrix Modification Following Retinal Ischemia/Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2008;49(13):6115.
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Retinal ischemia occurs in a variety of ocular conditions including central retinal artery occlusion and glaucoma and can cause irreversible vision loss. It has been shown that TGF-β signaling pathway is neuroprotective, and activated during astrocyte response to injury in the brain, and in glaucoma, and has an important role in neurodegeneration. The purpose of this study was to examine modifications in the TGF-β pathway, in the retina and optic nerve head in vivo in a rat model of retinal ischemia/reperfusion injury (RIRI). Manipulating TGF-β signaling pathway may provide potential therapeutic treatment to prevent vision loss after RIRI.
RIRI was induced in Sprague-Dawley rats by unilateral cannulation of the anterior chamber and elevation of the intraocular pressure (IOP) to 110 mm Hg for 60 min. RGC loss was quantified in the retina after retrograde labeling with Flourogold. RGC apoptosis was determined by TUNEL staining in retinal sections. The expression of TGF-β1, TGF-β2, and their receptors, TGFβRI and TGFβRII as well as matrix metalloproteases: MMP-2, and -9 and the extracellular matrix protein laminin was analyzed in the optic nerve head and in the retina by immunohistochemistry and western blotting. The gelatinolytic activity (MMP-2 and -9) was assayed by in situ zymography with a fluorogenic DQ gelatin substrate.
We determined increased expression of TGF-β1 in the optic nerve, and retina 1 and 5 days post-ischemia. While the TGF-β2 expression increased in the optic nerve head, it decreased in the retina. Additionally, we observed increased expression of both TGFβRI and TGFβRII in the retina and optic nerve, 1 and 5 days post-RIRI. MMP-9, but not MMP-2 expression was increased in the ganglion cell layer in the retina. Significant increase in gelatinolytic activity was detected in the retina 1 day post RIRI and correlated with degradation of laminin from the inner laminar membrane. Our analysis indicated that RGC loss in the ischemic eyes became apparent at 1 day, and reached 45% 5 days post-ischemia. RGC apoptosis peaked 1 day after RIRI.
This data suggests that TGF-β signaling is mainly up-regulated in the retina and optic nerve head after RIRI. In contrast to the optic nerve head we found a significant reduction in TGF-β2 expression in the retina. Since TGF-β2 is a negative regulator of MMP activity, we found increased MMP-9 activity, that results in laminin degradation in the retina. We established a causal link between TGF-β pathway, MMP-9, laminin degradation and RGC loss in the retina.
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