Purchase this article with an account.
Ruth B Caldwell, Zhimin Xu, S. Priya Narayanan, Tahira Lemtalsi, Chintan Patel, Esraa Shosha, William Caldwell; Arginase 2 deletion prevents optic nerve crush-induced retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1760.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
We have shown previously that deletion of the arginase 2 (A2) gene reduces neurovascular injury and improves retinal ganglion cell (RGC) survival in a model of ischemia/reperfusion injury. The aim of this study was to determine the role of A2 expression in traumatic retinal injury following optic nerve crush (ONC).
ONC was produced in the left eye of wild-type (WT) or A2 knockout (A2-/- ) mice by incising the limbal conjunctiva, deflecting the intraocular muscles and clamping the optic nerve (2 mm from the eyeball, 3 sec). The right eye served as sham control. Loss of ganglion cell layer (GCL) neurons and RGCs and microglial activation were assessed in retinal whole mounts labeled for the neuronal marker (NeuN), RCG marker (Brn3a) and microglia/macrophage marker (Iba1). Cell death, glial activation, and retinal thinning were assessed by TUNEL assay, GFAP immunostaining, and H&E staining of retinal sections, respectively. Molecular mechanisms were examined by western blotting and quantitative RT-PCR.
At 7 days after ONC, the number of NeuN positive neurons in the GCL of the WT retinas was decreased by 60% as compared to the sham controls. This ONC-induced neuronal loss was diminished in the A2-/- retinas (p<0.05). Brn3a-positive RGCs were significantly protected by A2 deletion (p<0.05). Significant retinal thinning was also seen in WT retinas following ONC, and this was blocked in A2-/- mice (p<0.01). Cell death studies showed an increase in TUNEL positive cells in the GCL after ONC in the WT retinas, and this was attenuated by A2 deletion. Activation of glial and microglial cells was elevated in WT retinas after ONC, and this was markedly reduced by A2 deletion. Western blotting showed that ONC also induced significant increases in levels of phosphorylated P38 and FASL in WT retinas compared with sham controls but not in the A2-/- mice (p<0.01). Quantitative RT-PCR showed that pro-inflammatory mediators (IL1β, ICAM1, MCP1, and NOX4) were upregulated following ONC in the WT retinas, and this was abrogated by A2 deletion.
Deletion of A2 limits ONC-induced neurodegeneration and glial activation by a mechanism involving decreases in retinal inflammation. These data demonstrate that A2 plays an important role in ONC-induced retinal damage. Blockade of A2 activity may offer a therapeutic strategy for preventing vision loss induced by traumatic retinal injury.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
This PDF is available to Subscribers Only