Abstract

Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.

Highlights

  • Age-related macular degeneration (AMD) is a blinding disease among people over the age of 50 worldwide

  • The results showed that the protein levels of Nod-like receptor pyrin-domain protein 3 (NLRP3) (Figures 1(e) and 1(g)), proCaspase-1 (Figures 1(f) and 1(j)) Caspase-1 (Figures 1(f) and 1(k)), and P2X7 receptor (P2X7R) (Figures 1(e) and 1(h)) and the phosphorylation of IKBα (Figures 1(e) and 1(i)) in ARPE-19 cells increased obviously after exposure to oxidized low-density lipoprotein (ox-low-density lipoprotein (LDL))

  • We investigated the effects of ox-LDL on proinflammatory responses and proangiogenesis in human ARPE-19 cells and in a novel mouse model presenting inflammatory responses and neovascularization

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Summary

Introduction

Age-related macular degeneration (AMD) is a blinding disease among people over the age of 50 worldwide. The prevalence of AMD is expected to increase dramatically as the global population ages [1]. AMD is closely related to chronic inflammation in retinal pigmented epithelial (RPE) cells, Bruch membrane, and choroid membrane [2]. There are two types of AMD according to the clinical characteristics, dry AMD and wet AMD. Dry AMD, called nonexudative AMD, is characterized by retinal inflammation, which mainly happens in the early stage of AMD. Wet AMD, called exudative AMD, is characterized by choroidal neovascularization and retinal angiogenesis, which usually happens in the late stage of AMD. Better understanding of the pathogenesis of AMD is crucial for seeking better and earlier treatment modalities

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