An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation

Abstract Glaucoma is a chronic and progressive neurodegenerative disease of the optic nerve resulting in loss of retinal ganglion cells (RGCs) and vision. The most prominent glaucoma risk factor is increased intraocular pressure (IOP), and most models focus on reproducing this aspect to study diseas...

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Autores principales:	David J. Mathew, Izhar Livne-Bar, Jeremy M. Sivak
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac18ebab4af045b2a21318f643d02dd3
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spelling	oai:doaj.org-article:ac18ebab4af045b2a21318f643d02dd32021-11-28T12:18:24ZAn inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation10.1038/s41598-021-02057-w2045-2322https://doaj.org/article/ac18ebab4af045b2a21318f643d02dd32021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02057-whttps://doaj.org/toc/2045-2322Abstract Glaucoma is a chronic and progressive neurodegenerative disease of the optic nerve resulting in loss of retinal ganglion cells (RGCs) and vision. The most prominent glaucoma risk factor is increased intraocular pressure (IOP), and most models focus on reproducing this aspect to study disease mechanisms and targets. Yet, current models result in IOP profiles that often do not resemble clinical glaucoma. Here we introduce a new model that results in a gradual and sustained IOP increase over time. This approach modifies a circumlimbal suture method, taking care to make the sutures ‘snug’ instead of tight, without inducing an initial IOP spike. This approach did not immediately affect IOPs, but generated gradual ocular hypertension (gOHT) as the sutures tighten over time, in comparison to loosely sutured control eyes (CON), resulting in an average 12.6 mmHg increase in IOP at 17 weeks (p < 0.001). Corresponding characterization revealed relevant retinal and optic nerve pathology, such as thinning of the retinal nerve fiber layer, decreased optokinetic response, RGC loss, and optic nerve head remodeling. Yet, angles remained open, with no evidence of inflammation. Corresponding biochemical profiling indicated significant increases in TGF-β2 and 3, and IL-1 family cytokines in gOHT optic nerve tissues compared to CON, with accompanying microglial reactivity, consistent with active tissue injury and repair mechanisms. Remarkably, this signature was absent from optic nerves following acute ocular hypertension (aOHT) associated with intentionally tightened sutures, although the resulting RGC loss was similar in both methods. These results suggest that the pattern of IOP change has an important impact on underlying pathophysiology.David J. MathewIzhar Livne-BarJeremy M. SivakNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David J. Mathew Izhar Livne-Bar Jeremy M. Sivak An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
description	Abstract Glaucoma is a chronic and progressive neurodegenerative disease of the optic nerve resulting in loss of retinal ganglion cells (RGCs) and vision. The most prominent glaucoma risk factor is increased intraocular pressure (IOP), and most models focus on reproducing this aspect to study disease mechanisms and targets. Yet, current models result in IOP profiles that often do not resemble clinical glaucoma. Here we introduce a new model that results in a gradual and sustained IOP increase over time. This approach modifies a circumlimbal suture method, taking care to make the sutures ‘snug’ instead of tight, without inducing an initial IOP spike. This approach did not immediately affect IOPs, but generated gradual ocular hypertension (gOHT) as the sutures tighten over time, in comparison to loosely sutured control eyes (CON), resulting in an average 12.6 mmHg increase in IOP at 17 weeks (p < 0.001). Corresponding characterization revealed relevant retinal and optic nerve pathology, such as thinning of the retinal nerve fiber layer, decreased optokinetic response, RGC loss, and optic nerve head remodeling. Yet, angles remained open, with no evidence of inflammation. Corresponding biochemical profiling indicated significant increases in TGF-β2 and 3, and IL-1 family cytokines in gOHT optic nerve tissues compared to CON, with accompanying microglial reactivity, consistent with active tissue injury and repair mechanisms. Remarkably, this signature was absent from optic nerves following acute ocular hypertension (aOHT) associated with intentionally tightened sutures, although the resulting RGC loss was similar in both methods. These results suggest that the pattern of IOP change has an important impact on underlying pathophysiology.
format	article
author	David J. Mathew Izhar Livne-Bar Jeremy M. Sivak
author_facet	David J. Mathew Izhar Livne-Bar Jeremy M. Sivak
author_sort	David J. Mathew
title	An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
title_short	An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
title_full	An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
title_fullStr	An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
title_full_unstemmed	An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
title_sort	inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ac18ebab4af045b2a21318f643d02dd3
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An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation

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