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Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis

Glaucoma is a chronic optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and the resulting mechanical stress are classically considered the main causes of RGC death. However, RGC degeneration and ensuing vision loss often...

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Autores principales: Amato, Rosario, Cammalleri, Maurizio, Melecchi, Alberto, Bagnoli, Paola, Porciatti, Vittorio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177096/
https://www.ncbi.nlm.nih.gov/pubmed/37174673
http://dx.doi.org/10.3390/cells12091272
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author Amato, Rosario
Cammalleri, Maurizio
Melecchi, Alberto
Bagnoli, Paola
Porciatti, Vittorio
author_facet Amato, Rosario
Cammalleri, Maurizio
Melecchi, Alberto
Bagnoli, Paola
Porciatti, Vittorio
author_sort Amato, Rosario
collection PubMed
description Glaucoma is a chronic optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and the resulting mechanical stress are classically considered the main causes of RGC death. However, RGC degeneration and ensuing vision loss often occur independent of IOP, indicating a multifactorial nature of glaucoma, with the likely contribution of glial and vascular function. The aim of the present study was to provide a comprehensive evaluation of the time course of neuro–glial–vascular changes associated with glaucoma progression. We used DBA/2J mice in the age range of 2–15 months as a spontaneous model of glaucoma with progressive IOP elevation and RGC loss typical of human open-angle glaucoma. We found that the onset of RGC degeneration at 10 months of age coincided with that of IOP elevation and vascular changes such as decreased density, increased lacunarity and decreased tight-junction protein zonula occludens (ZO)-1, while hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were already significantly upregulated at 6 months of age together with the onset of Müller cell gliosis. Astrocytes, however, underwent significant gliosis at 10 months. These results indicate that Müller cell activation occurs well before IOP elevation, with probable inflammatory consequences, and represents an early event in the glaucomatous process. Early upregulation of HIF-1α and VEGF is likely to contribute to blood retinal barrier failure, facilitating RGC loss. The different time courses of neuro–glial–vascular changes during glaucoma progression provide further insight into the nature of the disease and suggest potential targets for the development of efficient therapeutic intervention aside from IOP lowering.
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spelling pubmed-101770962023-05-13 Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis Amato, Rosario Cammalleri, Maurizio Melecchi, Alberto Bagnoli, Paola Porciatti, Vittorio Cells Article Glaucoma is a chronic optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and the resulting mechanical stress are classically considered the main causes of RGC death. However, RGC degeneration and ensuing vision loss often occur independent of IOP, indicating a multifactorial nature of glaucoma, with the likely contribution of glial and vascular function. The aim of the present study was to provide a comprehensive evaluation of the time course of neuro–glial–vascular changes associated with glaucoma progression. We used DBA/2J mice in the age range of 2–15 months as a spontaneous model of glaucoma with progressive IOP elevation and RGC loss typical of human open-angle glaucoma. We found that the onset of RGC degeneration at 10 months of age coincided with that of IOP elevation and vascular changes such as decreased density, increased lacunarity and decreased tight-junction protein zonula occludens (ZO)-1, while hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were already significantly upregulated at 6 months of age together with the onset of Müller cell gliosis. Astrocytes, however, underwent significant gliosis at 10 months. These results indicate that Müller cell activation occurs well before IOP elevation, with probable inflammatory consequences, and represents an early event in the glaucomatous process. Early upregulation of HIF-1α and VEGF is likely to contribute to blood retinal barrier failure, facilitating RGC loss. The different time courses of neuro–glial–vascular changes during glaucoma progression provide further insight into the nature of the disease and suggest potential targets for the development of efficient therapeutic intervention aside from IOP lowering. MDPI 2023-04-27 /pmc/articles/PMC10177096/ /pubmed/37174673 http://dx.doi.org/10.3390/cells12091272 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Amato, Rosario
Cammalleri, Maurizio
Melecchi, Alberto
Bagnoli, Paola
Porciatti, Vittorio
Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
title Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
title_full Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
title_fullStr Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
title_full_unstemmed Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
title_short Natural History of Glaucoma Progression in the DBA/2J Model: Early Contribution of Müller Cell Gliosis
title_sort natural history of glaucoma progression in the dba/2j model: early contribution of müller cell gliosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177096/
https://www.ncbi.nlm.nih.gov/pubmed/37174673
http://dx.doi.org/10.3390/cells12091272
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