Abstract
Age-related macular degeneration (AMD) is a leading cause of vision loss. Elevated homocysteine (Hcy) (Hyperhomocysteinemia) (HHcy) has been reported in AMD. We previously reported that HHcy induces AMD-like features. This study suggests that N-Methyl-d-aspartate receptor (NMDAR) activation in the retinal pigment epithelium (RPE) is a mechanism for HHcy-induced AMD. Serum Hcy and cystathionine-β-synthase (CBS) were assessed by ELISA. The involvement of NMDAR in Hcy-induced AMD features was evaluated (1) in vitro using ARPE-19 cells, primary RPE isolated from HHcy mice (CBS), and mouse choroidal endothelial cells (MCEC); (2) in vivo using wild-type mice and mice deficient in RPE NMDAR (NMDARR−/−) with/without Hcy injection. Isolectin-B4, Ki67, HIF-1α, VEGF, NMDAR1, and albumin were assessed by immunofluorescence (IF), Western blot (WB), Optical coherence tomography (OCT), and fluorescein angiography (FA) to evaluate retinal structure, fluorescein leakage, and choroidal neovascularization (CNV). A neovascular AMD patient’s serum showed a significant increase in Hcy and a decrease in CBS. Hcy significantly increased HIF-1α, VEGF, and NMDAR in RPE cells, and Ki67 in MCEC. Hcy-injected WT mice showed disrupted retina and CNV. Knocking down RPE NMDAR improved retinal structure and CNV. Our findings underscore the role of RPE NMDAR in Hcy-induced AMD features; thus, NMDAR inhibition could serve as a promising therapeutic target for AMD.
Highlights
Age-related macular degeneration (AMD) is a leading cause of vision loss in people over 60 [1,2]
We propose that NMDAR activation in the retinal pigment epithelium (RPE) cells by HHcy plays a fundamental role in AMD induction, and that blocking NMDAR in RPE could be a novel therapeutic target for patients with AMD
The current study presents evidence suggesting that the activation of NMDAR as a possible mechanism of HHcy-induced blood retinal barrier (BRB) dysfunction, features of AMD and choroidal neovascularization (CNV)
Summary
Age-related macular degeneration (AMD) is a leading cause of vision loss in people over 60 [1,2]. Around 11 million new AMD patients are diagnosed every year in the United States [3]. The United States spends around USD 255 billion for AMD health care. AMD is the primary cause of visual disability in the developed world and third globally [4]. It is essential these days to find a new therapy for AMD. The major treatment options that have been developed in the last decades to treat the wet form of AMD are targeting the angiogenesis through anti-VEGF therapy. These AMD treatments are still unable to cure AMD; patients require unlimited treatment and do not regain their vision
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