[PMID]: | 28877319 |
[Au] Autor: | Wang J; Saul A; Cui X; Roon P; Smith SB |
[Ad] Endereço: | Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States. |
[Ti] Título: | Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa. |
[So] Source: | Invest Ophthalmol Vis Sci;58(11):4545-4558, 2017 Sep 01. |
[Is] ISSN: | 1552-5783 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Purpose: Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R-/- mice have late-onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration. Methods: Wild-type, rd10, and rd10/Sig1R-/- mice were subjected to ERG and spectral-domain optical coherence tomography (SD-OCT) to assess visual function/structure in situ. Retinas imaged microscopically were subjected to morphometric analysis, immunodetection of cones, and analysis of gliosis. Oxidative and endoplasmic reticulum (ER) stress was evaluated at mRNA/protein levels. Results: Photopic ERG responses were reduced significantly in rd10/Sig1R-/- versus rd10 mice at P28 (31 ± 6 vs. 56 ± 7 µV), indicating accelerated cone loss when Sig1R was absent. At P28, SD-OCT revealed reduced retinal thickness in rd10/Sig1R-/- mice (60% of WT) versus rd10 (80% of WT). Morphometric analysis disclosed profound photoreceptor nuclei loss in rd10/Sig1R-/- versus rd10 mice. rd10/Sig1R-/- mice had 35% and 60% fewer photoreceptors, respectively, at P28 and P35, than rd10. Peanut agglutinin cone labeling decreased significantly; gliosis increased significantly in rd10/Sig1R-/- versus rd10 mice. At P21, NRF2 levels increased in rd10/Sig1R-/- mice versus rd10 and downstream antioxidants increased indicating oxidative stress. At P28, ER stress genes/proteins, especially XBP1, a potent transcriptional activator of the unfolded protein response and CHOP, a proapoptotic transcription factor, increased significantly in rd10/Sig1R-/- mice versus rd10. Conclusions: Photoreceptor cell degeneration accelerates and cone function diminishes much earlier in rd10/Sig1R-/- than rd10 mice emphasizing the importance of Sig1R as a modulator of retinal cell survival. |
[Mh] Termos MeSH primário: |
Apoptose Modelos Animais de Doenças Receptores sigma/fisiologia Células Fotorreceptoras Retinianas Cones/patologia Células Fotorreceptoras Retinianas Bastonetes/patologia Retinite Pigmentosa/patologia
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[Mh] Termos MeSH secundário: |
Animais Eletrorretinografia Feminino Técnica Indireta de Fluorescência para Anticorpo Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Estresse Oxidativo Retina/fisiologia Tomografia de Coerência Óptica
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Receptors, sigma); 0 (sigma-1 receptor) |
[Em] Mês de entrada: | 1709 |
[Cu] Atualização por classe: | 170919 |
[Lr] Data última revisão:
| 170919 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170907 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1167/iovs.17-21947 |
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