Purchase this article with an account.
S. P. Narayanan, J. Suwanpradid, W. Zhang, Z. Xu, S. E. Brooks, R. W. Caldwell, R. B. Caldwell; Arginase Depletion Modulates Akt and iNOS to Reduce Retinal Degeneration in a Mouse Model of Retinopathy of Prematurity. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4482.
Download citation file:
© 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 genes results in a significant decrease in hyperoxia-induced vaso-obliteration (Suwanpradid et al, ARVO 2010 submitted). The aim of the current study was to determine whether arginase deletion also protects against retinal degeneration during OIR.
Newborn wild-type (WT) and arginase knockout mice deficient in arginase-2 (A2-/-) alone or in combination with haplo-insufficiency of arginase 1 (A1+/- 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 were prepared for immunohistochemical analysis of GFAP, glutamine synthetase,Akt and iNOS expression, as well as morphometric analysis and TUNEL labeling of apoptotic cells.
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 (212±16µm vs 313.±24µm, p<0.001 and 43±6 µm vs 82±3µm, p<0.001, respectively). The retinal thinning was significantly reduced in the A2-/- and A1+/- A2-/- mice (P<0.05). Glial activation (measured by increased expression of GFAP and glutamine synthetase) was reduced in both knockout lines compared to WT OIR mice, while Akt activity in the inner nuclear layer of arginase deficient mice was higher. In contrast, the increased expression of retinal iNOS observed in WT OIR mice was markedly reduced in the arginase knockout mice.
Our data suggest that retinal arginase activity is involved in reduced neuronal survival in OIR. Deletion of arginase improves neuronal survival in during retinal ischemia, possibly through the increased activity of Akt and concomitant suppression of iNOS expression. These molecular events are associated with decreased activation of Muller cells, suggesting a rescue effect on macroglia as well.
This PDF is available to Subscribers Only