{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:36Z","timestamp":1787028456646,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY029751-01\u2013NEI00072 and R01 EY030054"],"award-info":[{"award-number":["R01 EY029751-01\u2013NEI00072 and R01 EY030054"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-\u03b2-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\u2212\/\u2212) with\/without Hcy injection. Isolectin-B4, Ki67, HIF-1\u03b1, 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\u2019s serum showed a significant increase in Hcy and a decrease in CBS. Hcy significantly increased HIF-1\u03b1, 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.<\/jats:p>","DOI":"10.3390\/ijms22179356","type":"journal-article","created":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T21:45:16Z","timestamp":1630273516000},"page":"9356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Implication of N-Methyl-d-Aspartate Receptor in Homocysteine-Induced Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"22","author":[{"given":"Yara A.","family":"Samra","sequence":"first","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Kira","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragya","family":"Rajpurohit","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyaz","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia (MCG), Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3802-3868","authenticated-orcid":false,"given":"Leah A.","family":"Owen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Jacobs School of Medicine and Biomedical Engineering, SUNY-University at Buffalo, Buffalo, NY 14214, USA"},{"name":"Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT 84108, USA"},{"name":"Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akbar","family":"Shakoor","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana K.","family":"Kim","sequence":"additional","affiliation":[{"name":"Retina Service, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3731-142X","authenticated-orcid":false,"given":"Margaret M.","family":"DeAngelis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Jacobs School of Medicine and Biomedical Engineering, SUNY-University at Buffalo, Buffalo, NY 14214, USA"},{"name":"Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT 84108, USA"},{"name":"Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"},{"name":"VA Western New York Healthcare System, Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-9217","authenticated-orcid":false,"given":"Nader","family":"Sheibani","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Visual Sciences and Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Al-Shabrawey","sequence":"additional","affiliation":[{"name":"Department of Foundational Medical Studies and Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA"},{"name":"Eye Research Institute, Oakland University, Rochester, MI 48309, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0245-8256","authenticated-orcid":false,"given":"Amany","family":"Tawfik","sequence":"additional","affiliation":[{"name":"Department of Foundational 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