Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness with limited effective treatment. Although the pathogenesis of this disease is complex and not fully understood, the oxidative damage caused by excessive reactive oxygen species (ROS) in retinal pigment epithelium (RPE) has been considered as a major cause. Autophagy is essential for the degradation of cellular components damaged by ROS, and its dysregulation has been implicated in AMD pathogenesis. Therefore, strategies aiming to boost autophagy could be effective in protecting RPE cells from oxidative damage. Metformin is the first-line anti-type 2 diabetes drug and has been reported to stimulate autophagy in many tissues. We therefore hypothesized that metformin may be able to protect RPE cells against H2O2-induced oxidative damage by autophagy activation. In the present study, we found that metformin attenuated H2O2-induced cell viability loss, apoptosis, elevated ROS levels, and the collapse of the mitochondria membrane potential in D407 cells. Autophagy was stimulated by metformin, and inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) or knockdown of Beclin1 and LC3B blocked the protective effects of metformin. In addition, we showed that metformin could activate the AMPK pathway, whereas both pharmacological and genetic inhibitions of AMPK blocked the autophagy-stimulating and protective effects of metformin. Metformin conferred a similar protection against H2O2-induced oxidative damage in primary cultured human RPE cells. Taken together, these results demonstrate that metformin could protect RPE cells from H2O2-induced oxidative damage by stimulating autophagy via the activation of the AMPK pathway, supporting its potential use in the prevention and treatment of AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over 50 years of age
We aimed to investigate whether metformin could protect retinal pigment epithelium (RPE) cells from H2O2induced oxidative damage and whether the protective effects are associated with the upregulation of autophagy promoted by AMPK activation
The pathogenesis of AMD is complex, RPE degeneration caused by oxidative damage has been considered a major cause of this condition
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over 50 years of age. Late AMD can be divided into neovascular (wet) and nonneovascular (dry) forms [1]. Therapies such as antivascular endothelial growth factor (anti-VEGF) therapy have been proven to be effective in treating wet AMD [2]. The pathogenesis of dry AMD is complex, the degeneration of the aging retinal pigment epithelium (RPE) cells is widely considered to be the initial event [3]. Studies have been showing that RPE cell impairment can lead to the accumulation of damaged organelles and various nonfunctional or toxic proteins, including lipofuscin, and promote the formation of drusen which is a typical characteristic of AMD [11]
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