Accelerated Retinal Degeneration and Progressive RPE Dystrophy by Oxidative Stress in a Retinal Angiomatous Proliferation (RAP) Model

Abstract

Purpose: : Oxidative stress has been identified as a key mechanism in leading to retinal degeneration in the vldlr null mouse¹. The purpose of this study is to determine if the level of retinal degeneration in vldlr deficient mouse is enhanced by removal of sod1 gene.

Methods: : vldlr null mice were back crossed onto the sod1 leb/j C57b/6 null background and the levels of RPE dystrophy, retinal function, and neovascular response followed at 4 and 6 months of age. RPE dystrophy was monitored by both color fundus and I/R imaging using HRA2 SLO fitted with a 55^o lens. Neovascularization was monitored by flourescien angiography. Retinal Structural and functional changes were monitored by H&E staining, OCT and scotopic ERG.

Results: : Consistent with observations reported in the literature¹ vldlr null mice showed modest deficits in scotopic ERG at 4 and 6 months of age. Sod1 -/- mice had no loss in scotopic A and B wave amplitudes. However, vldlr/sod1 double knockout mice had a significantly decreased scotopic A and B wave amplitudes and oscillatory potential relative to wild type, sod1 -/- or vldlr -/- animals by 2 months. Examination of sod -/- and sod -/+ on a vldlr null background indicated that the level of functional deficit was dependent on sod1 copy number. The functional deficits observed by ERG correlated with a significant reduction in ONL thickness as measured by OCT and H&E staining. Color fundus identified localized RPE dystrophy in the vldlr -/- mice while in the sod1/vldlr double knockout a wide-spread RPE dystrophy was observed. Angiography indicated similar patterns of subretinal neovascularization in both the vldlr -/- and the vldlr/sod1 double knockout mice.

Conclusions: : Reduction in anti-oxidant defense through removal of the sod1 gene significantly accelerated the functional deficits see in the vldlr -/- animals. The level of deficit was coupled to the presence of the sod1 gene with sod-/- showing greater loss than sod-/+ animals suggesting a direct effect of oxidative stress mechanism on photoreceptor function. Unique to our observations was the pronounced expansion of RPE dystrophy in the DKO mouse.¹ J. Clin. Invest 119:611-623(2009)

Keywords: choroid: neovascularization • oxidation/oxidative or free radical damage • degenerations/dystrophies