Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Dry AMD is characterized by a progressive macular degeneration of the retinal pigment epithelium (RPE) and photoreceptors, and the RPE oxidative damage/dystrophy is at the core of the disease. Recent population/patients-based studies have shown an association of high free serum thyroid hormone (TH) levels with increased risk of AMD. This work investigated the effects of TH signaling inhibition on RPE and photoreceptor damage/cell death in an oxidative stress-induced mouse model of AMD. TH signaling inhibition was achieved by anti-thyroid drug treatment and oxidative stress was induced by sodium iodate (NaIO3) administration. Mice treated with NaIO3 showed severe RPE and photoreceptor cell death/necroptosis, destruction, oxidative damage, retinal stress, and reduced retinal function. Treatment with anti-thyroid drug protected RPE and photoreceptors from damage/cell death induced by NaIO3, reduced oxidative damage of RPE and photoreceptors, and preserved retinal function. Gene expression analysis showed that the NaIO3-induced RPE/photoreceptor damage/cell death involves multiple mechanisms, including cellular oxidative stress responses, activation of necroptosis/apoptosis signaling, and inflammatory responses. Treatment with anti-thyroid drug abolished these cellular stress/death responses. The findings of this study demonstrate a role of TH signaling in RPE and photoreceptor cell death after oxidative stress challenge, and support a role of TH signaling in the pathogenesis of AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly, exhibiting complex interplay of genetic and environmental factors[1,2]
To determine the role of Thyroid hormone (TH) signaling in oxidative stress-induced damage and cell death, we examined the effects of anti-thyroid treatment in mice that have been treated with NaIO3
retinal pigment epithelium (RPE) morphology and cell loss were evaluated by phalloidin staining for F-actin and DAPI staining for nucleus on RPE whole mounts at 2–3 days post-NaIO3 injection. a, b Shown are RPE morphology evaluations in P30 mice. a Shown are representative low magnification images of phalloidin staining and corresponding quantitative analysis of the damaged area in the RPE. b Shown are representative high magnification images of phalloidin staining and DAPI labeling taken at different regions of the RPE, and corresponding quantitative analysis of RPE cell numbers and RPE nuclear numbers
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly, exhibiting complex interplay of genetic and environmental factors[1,2]. There are two types of AMD, the dry and wet forms. Dry AMD, known as geographic atrophy, is a form of slowly progressing geographic atrophy of the macula, and comprises a majority of AMD cases (∼90%), whereas wet AMD rapidly progresses to blindness and involves the abnormal formation of blood vessels in the macula. Dry AMD is Thyroid hormone (TH) signaling regulates numerous physiological functions, including cell growth, differentiation, and metabolic homeostasis. TH signaling regulates cone opsin expression[5,6] and cone photoreceptor viability[7,8,9,10]. TH signaling has Official journal of the Cell Death Differentiation Association
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