Retinal Dysfunction and Progressive Retinal Cell Death in SOD1-Deficient Mice

Abstract

The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase (SOD1) in mice leads to many different phenotypes that resemble accelerated aging. The purpose of this study was to examine the morphology and physiology of the sensory retina in Sod1 ؊/؊ mice. The amplitudes of the a-and b-waves of electroretinograms elicited by stimuli of different intensity were reduced in senescent Sod1 ؊/؊ mice, and this reduction in amplitude was more pronounced with increasing age. Retinal morphometric analyses showed a reduced number of nuclei in both the inner nuclear cell layer and outer nuclear cell layer. Electron microscopy revealed swollen cells and degenerated mitochondria in the inner nuclear cell and outer nuclear cell layer of senescent Sod1 ؊/؊ mice indicating necrotic cell death. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed no significant differences in the number of apoptotic cells between Sod1 ؊/؊ and wild-type mice, and activated caspase-3 could not be detected in the retina of Sod1 ؊/؊ mice. In addition to the age-related macular degeneration-like phenotypes previously reported, Sod1 ؊/؊ mice also present progressive retinal degeneration. Our results indicate that Sod1 ؊/؊ mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated retinal degeneration. The superoxide dismutase (SOD) family is one of the main antioxidant systems in the body and is made up of the three SOD isoenzymes; Cu,Zn-superoxide dismutase (SOD1) exists in the cytoplasm, SOD2 or Mn-SOD in the mitochondrial matrix, and SOD3 or extracellular SOD in the interstitium of tissues as the secreted form.1 SOD1 catalyzes superoxide radical dismutation and is distributed throughout the body, 1 and among the three isozymes, it is the most abundant in the retina.2 This suggests that SOD1 may be important in protecting the sensory retina from the reactive oxygen species (ROS)-mediated retinal damage.Many models of retinal degeneration have been studied 3,4 ; however, the mechanism of retinal cell deaths in some of these models has still not been determined. Cell death can be either necrotic or apoptotic, and necrotic cell death is characterized by a swelling of the cell membranes and organelles that leads to a disruption of the cell membranes and lysis. These alterations subsequently lead to inflammatory responses. 5 Apoptosis is a process of programmed cell death, and involves an orchestrated series of biochemical events leading to characteristic cell morphology and death. In some models of retinal degeneration, the death of the neurons has been shown to be attributable to apoptosis. 6 -8 SOD1 deficiency (Sod1 Ϫ/Ϫ ) leads to many different phenotypes resembling aging, and the changes are attributable to an elevation of ROS. 9,10 We recently reported that senescent Sod1 Ϫ/Ϫ mice had features of age-related macular degeneration (AMD) including the presence of drusen, choroidal neovascularization, and retinal pigment epithelium d...

Living Beyond Our Physiological Means

“…109 Transgenic mice overexpressing vascular endothelial growth factor have also been used to model ARMD. 110 Finally, Tsubota and colleagues 111,112 showed that mice deficient in Cu, Zn-superoxide dismutase have features typical of the human form of ARMD.…”

The Protective Effects of a Dietary Carotenoid, Astaxanthin, Against Light-Induced Retinal Damage

“…Previous reports have indicated that light exposure induces Sod1 (8) and that the retinas of Sod-1-knockout mice are likely to be impaired by light exposure (9), suggesting that light exposure induces ROS in the retina and evokes retinal degeneration. ROS is related to the regulation of many principal cell functions such as activation of transcription factor (35), gene expression (36), and cell proliferation (37).…”

“…It is known that ROS is produced by light exposure in the retina, and it evokes photoreceptor degeneration (8,9); thus, antioxidants such as dimethylthiourea (10), phenyl-N-tert-butyl nitrone (11), and 2,2,6,6-tetramethyl-4-piperidinol-1-oxyl (12) have been reported to be effective in animal experiments. Astaxanthin, a carotenoid, is present in many wellknown seafoods such as salmon, trout, red sea-bream, shrimp, lobster, and fish eggs.…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…This may amplify the inflammatory process leading to additional RPE cell damage, potentially producing a state of chronic inflammation . Knockout of antioxidative genes in mice (Sod1À/À mice, Sod2 knockdown mice, and Nrf2À/À mice) results in the development of the typical features of AMD (Hashizume et al 2008;). Genetically, polymorphism in a number of genes, including members of the complement pathway, apolipoprotein E (ApoE), ARMS2, HTRA1, CX3CR1, VEGF-A, and ABCA4 have been associated with AMD, indicating the involvement of inflammation, lipid metabolism, RPE dysfunction, and angiogenesis in AMD (Ding et al 2009).…”