Abstract
BackgroundRetinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are also affected. This study was undertaken to determine the role of the mitochondrial arginine/ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP.Methods and FindingsStudies were performed using wild type (WT) and A2 knockout (A2−/−) mice exposed to Oxygen Induced Retinopathy (OIR). Neuronal injury and apoptosis were assessed using immunohistochemistry, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end) labeling and Western blotting. Electroretinography (ERG) was used to assess retinal function. Neuro-glial injury in WT ROP mice was evident by TUNEL labeling, retinal thinning, decreases in number of rod bipolar cells and glial cell activation as compared with room air controls. Significant reduction in numbers of TUNEL positive cells, inhibition of retinal thinning, preservation of the rod bipolar cells and prevention of glial activation were observed in the A2−/− retinas. Retinal function was markedly impaired in the WT OIR mice as shown by decreases in amplitude of the b-wave of the ERG. This defect was significantly reduced in A2−/− mice. Levels of the pro-apoptotic proteins p53, cleaved caspase 9, cytochrome C and the mitochondrial protein Bim were markedly increased in WT OIR retinas compared to controls, whereas the pro-survival mitrochondrial protein BCL-xl was reduced. These alterations were largely blocked in the A2−/− OIR retina.ConclusionsOur data implicate A2 in neurodegeneration during ROP. Deletion of A2 significantly improves neuronal survival and function, possibly through the regulation of mitochondrial membrane permeability mediated apoptosis during retinal ischemia. These molecular events are associated with decreased activation of glial cells, suggesting a rescue effect on macroglia as well.
Highlights
Retinopathy of prematurity (ROP) is a major cause of childhood vision impairment in developed countries
Retinal degeneration was studied in double knockout mice lacking one copy of Arginase 1 (A1) as well as both copies of arginase 2 (A2) (A1+/2 A22/2, deletion of both copies of A1 is lethal at P10–14)
Both retinal and inner nuclear layer (INL) thickness were comparable to that in the A22/2 Oxygen Induced Retinopathy (OIR) mice. These results demonstrate that A2 plays an important role in the neurodegeneration during OIR
Summary
Retinopathy of prematurity (ROP) is a major cause of childhood vision impairment in developed countries. Despite effective treatment of the vascular injury, many children suffer vision impairment suggesting a disruption of neuronal development [1]. Recent study has shown that the function of the post receptor neural retina is significantly impaired in a rat model of ROP [8,9]. Retinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are affected. This study was undertaken to determine the role of the mitochondrial arginine/ ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
