Abstract
Subretinal fibrosis is a common pathological change that causes vision loss in neovascular age-related macular degeneration (nAMD). Treatment modalities for subretinal fibrosis are limited. In the present study, the effects of fenofibrate, a specific peroxisome proliferator–activated receptor alpha agonist, on subretinal fibrosis of nAMD were tested, and its molecular mechanisms of action were delineated. Collagen deposition and protein expression of fibrotic markers, such as vimentin, collagen-1, alpha-smooth muscle actin, and fibronectin, were increased in very low–density lipoprotein receptor (VLDLR) knockout mouse, indicating Vldlr −/− mice can be used as a model for subretinal fibrosis. Fenofibrate suppressed subretinal fibrosis of Vldlr −/− mice by reducing collagen deposition and protein expression of fibrotic markers. Two fibrotic pathways, TGF-β—Smad2/3 signaling and Wnt signaling, were significantly up-regulated, while inhibited by fenofibrate in Vldlr −/− retinas. Moreover, fenofibrate significantly reduced the downstream connective tissue growth factor (CTGF) expression of these two pathways. Müller cells were a major source of CTGF in Vldlr −/− retinas. Fenofibrate was capable of suppressing Müller cell activation and thus reducing the release of CTGF in Vldlr −/− retinas. In cultured Müller cells, fenofibrate reversed TGF-β2–induced up-regulation of Wnt signaling and CTGF expression. These findings suggested that fenofibrate inhibits subretinal fibrosis by suppressing TGF-β—Smad2/3 signaling and Wnt signaling and reducing CTGF expression, and thus, fenofibrate could be a potential treatment for nAMD with subretinal fibrosis.
Highlights
Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly of Western societies (Lim et al, 2012)
These results indicate the presence of subretinal fibrosis in the retina of very low–density lipoprotein receptor (Vldlr)−/− mice, which could be used as a mouse model of subretinal fibrosis
We have identified the presence of subretinal fibrosis in the Vldlr−/− mouse, indicating Vldlr−/− mouse is a useful tool for studying retinal fibrosis
Summary
Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly of Western societies (Lim et al, 2012). Anti-VEGF drugs have been standardized for the treatment of nAMD. More than 10% patients are unresponsive to anti-VEGF treatment and may progress to subretinal fibrous scar formation and massive subretinal hemorrhage (Kovach et al, 2012). The process of subretinal fibrosis involves excessive response to tissue damage, proliferation, and infiltration of various cell types, including retinal pigment epithelial (RPE) cells, glial cells, macrophages, and fibroblasts, and formation of extracellular matrix (ECM) (Ishikawa et al, 2016). The formation of subretinal fibrosis disrupts the physical connections of retinal cells and results in abnormal functioning of retina, and even loss of function (Ishikawa et al, 2016). The molecular mechanisms of subretinal fibrosis are still unclear, and the clinical treatment for subretinal fibrosis is very limited, especially for the late-stage nAMD
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