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S Priya Narayanan, Jutamas Suwanpradid, Alan Saul, Zhimin Xu, Amber Still, Tahira Lemtalsi, Robert W. Caldwell, Ruth B. Caldwell; Deletion of Arginase 2 Reduces Neurodegeneration and Improves Retinal Function in a Mouse Model of Retinopathy of Prematurity via P53 Dependant Pathway. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3936. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) is a major cause of vascular injury in premature infants. Studies indicate that retinal neurons are also affected in ROP. Using an oxygen-induced retinopathy (OIR) model for ROP, we found that deletion of the arginase 2 (Arg 2) gene results in a significant decrease in retinal degeneration and glial injury (Narayanan et al, ARVO 2010). The aim of the current study was to determine the impact of Arg 2 deletion on retinal function during OIR and to elucidate the neuroprotective mechanism
Newborn wild-type (WT) and knockout mice deficient in Arg 2 (A2-/-) were used. Mice were maintained in 70% oxygen from postnatal day 7 to 12 followed by normoxia from day 12 to 17. Retinal cryostat sections or homogenates were prepared for immunohistochemstry, morphometric analysis, TUNEL labeling of apoptotic cells and Western blotting. Electroretinography (ERG) was used to assess retinal function.
Retinal degeneration in WT OIR mice was evident by TUNEL labeling as well as significant thinning of the retina and inner nuclear layer compared to room air controls (P<0.01). Number of rod bipolar cells (measured by PKCα immunoreactivity) was also significantly reduced in the WT OIR mice. Significant reduction in numbers of TUNEL positive cells, prevention of retinal thinning and preservation of the rod bipolar cells (p<0.05) were observed in the A2-/- mice. Glial activation (measured by increased expression of GFAP) was significantly also reduced in A2-/- retina compared to WT OIR mice. Retinal function in the WT OIR mice was markedly impaired as shown by decreases in the b-wave of the ERG. This defect was significantly reversed in A2-/- OIR mice (P< 0.05). Levels of P53, cytochrome C and cleaved caspase-9 were markedly increased in WT OIR retinas compared to WT control. These alterations were largely reversed in the A2-/- OIR retinas.
Our data demonstrate that retinal Arg 2 is involved in the neurodegeneration associated with OIR. Deletion of Arg 2 significantly improves neuronal survival and function in OIR, possibly through the regulation of mitochondrial membrane permeability mediated apoptosis during retinal ischemia. These molecular events are associated with decreased activation of Muller cells, suggesting a rescue effect on macroglia as well.
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