NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells
DC Field | Value | Language |
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dc.contributor.author | Lee, Jae Rim | - |
dc.contributor.author | Jeong, Kwang Won | - |
dc.date.accessioned | 2022-09-27T06:40:27Z | - |
dc.date.available | 2022-09-27T06:40:27Z | - |
dc.date.created | 2022-09-22 | - |
dc.date.issued | 2022-08 | - |
dc.identifier.issn | 1010-660X | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/85569 | - |
dc.description.abstract | Background and Objectives: Age-related macular degeneration is a slow-progressing disease in which lipofuscin accumulates in the retina, causing inflammation and apoptosis of retinal pigment epithelial (RPE) cells. This study aimed to identify N-methyl-D-aspartate (NMDA) signaling as a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. Materials and Methods: A2E degradation assays were performed in ARPE-19 cells using fluorescently labeled A2E. The autophagic activity in ARPE-19 cells was measured upon blue light (BL) exposure, after A2E treatment. Autophagy flux was determined by measuring LC3-II formation using immunoblotting and confocal microscopy. To determine whether autophagy via the NMDA receptor is involved in A2E clearance, ATG5-deficient cells were used. Results: Ro 25-6981, an NR2B-selective NMDA receptor antagonist, effectively cleared A2E. Ro 25-6981 reduced A2E accumulation in the lysosomes of ARPE-19 cells at sub-cytotoxic concentrations, while increasing the formation of LC3-II and decreasing p62 protein levels in a concentration-dependent manner. The autophagic flux monitored by RFP-GFP-LC3 and bafilomycin A1 assays was significantly increased by Ro 25-6981. A2E clearance by Ro 25-6981 was abolished in ATG5-depleted ARPE-19 cells, suggesting that A2E degradation by Ro 25-6981 was mediated by autophagy. Furthermore, treatment with other NMDA receptor antagonists, CP-101,606 and AZD6765, showed similar effects on autophagy activation and A2E degradation in ARPE-19 cells. In contrast, glutamate, an NMDA receptor agonist, exhibited a contrasting effect, suggesting that both the activation of autophagy and the degradation of A2E by Ro 25-6981 in ARPE-19 cells occur through inhibition of the NMDA receptor pathway. Conclusions: This study demonstrates that NMDA receptor antagonists degrade lipofuscin via autophagy in human RPE cells and suggests that NMDA receptor antagonists could be promising new therapeutics for retinal degenerative diseases. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | MDPI | - |
dc.relation.isPartOf | MEDICINA-LITHUANIA | - |
dc.title | NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000845487700001 | - |
dc.identifier.doi | 10.3390/medicina58081129 | - |
dc.identifier.bibliographicCitation | MEDICINA-LITHUANIA, v.58, no.8 | - |
dc.description.isOpenAccess | Y | - |
dc.identifier.scopusid | 2-s2.0-85136628845 | - |
dc.citation.title | MEDICINA-LITHUANIA | - |
dc.citation.volume | 58 | - |
dc.citation.number | 8 | - |
dc.contributor.affiliatedAuthor | Lee, Jae Rim | - |
dc.contributor.affiliatedAuthor | Jeong, Kwang Won | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | retinal pigment epithelial cells | - |
dc.subject.keywordAuthor | drusen | - |
dc.subject.keywordAuthor | N-retinylidene-N-retinylethanolamine (A2E) | - |
dc.subject.keywordAuthor | N-methyl-D-aspartate (NMDA) | - |
dc.subject.keywordAuthor | autophagy | - |
dc.subject.keywordPlus | MACULAR DEGENERATION | - |
dc.subject.keywordPlus | WET AMD | - |
dc.subject.keywordPlus | A2E | - |
dc.subject.keywordPlus | FLUOROPHORE | - |
dc.subject.keywordPlus | DEATH | - |
dc.subject.keywordPlus | RPE | - |
dc.subject.keywordPlus | ACCUMULATION | - |
dc.subject.keywordPlus | INFLAMMATION | - |
dc.subject.keywordPlus | MECHANISMS | - |
dc.subject.keywordPlus | PROTECTION | - |
dc.relation.journalResearchArea | General & Internal Medicine | - |
dc.relation.journalWebOfScienceCategory | Medicine, General & Internal | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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