Implication of n-methyl-D-aspartate receptor in homocysteine-induced age-related macular degeneration

Yara A. Samra, Dina Kira, Pragya Rajpurohit, Riyaz Mohamed, Leah A. Owen, Akbar Shakoor, Ivana K. Kim, Margaret M. Deangelis, Nader Sheibani, Mohamed Al-Shabrawey, Amany Tawfik

Research output: Contribution to journalArticlepeer-review

Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss. Elevated ho-mocysteine (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 neo-vascular 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.

Original languageEnglish (US)
Article number9356
JournalInternational journal of molecular sciences
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2021
Externally publishedYes

Keywords

  • Age-related macular degeneration
  • Blood retinal barrier
  • Cystathionine-β-synthase
  • Homocysteine
  • Mouse
  • N-methyl-D-aspartate receptor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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