Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma

Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular...

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Autores principales:	Ramesh B. Kasetti, Prabhavathi Maddineni, Bindu Kodati, Bhavani Nagarajan, Sam Yacoub
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	astragaloside IV trabecular meshwork TGFβ2 myocilin ECM MMP Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/90f5095072a24a44916bcf28d17786b3
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spelling	oai:doaj.org-article:90f5095072a24a44916bcf28d17786b32021-11-25T17:57:22ZAstragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma10.3390/ijms2222125081422-00671661-6596https://doaj.org/article/90f5095072a24a44916bcf28d17786b32021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12508https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular matrix (ECM) production, deposition and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) contribute to increased aqueous humor (AH) outflow resistance and IOP elevation. Drugs which alter the glaucomatous fibrotic changes and ER stress in the TM may be effective in reducing ocular hypertension. Astragaloside IV (AS.IV), a novel saponin isolated from the roots of <i>Astragalus membranaceus</i>, has demonstrated antifibrotic and ER stress lowering effects in various tissues during disease conditions. However, the effect of AS.IV on glaucomatous TM fibrosis, ER stress and ocular hypertension has not been studied. Primary human TM cells treated with AS.IV decreased TGFβ2 induced ECM (FN, Col-I) deposition and ER stress (KDEL, ATF4 and CHOP). Moreover, AS.IV treatment reduced TGFβ2 induced NF-κB activation and αSMA expression in TM cells. We found that AS.IV treatment significantly increased levels of matrix metalloproteases (MMP9 and MMP2) and MMP2 enzymatic activity, indicating that the antifibrotic effects of AS.IV are mediated via inhibition of NF-κB and activation of MMPs. AS.IV treatment also reduced ER stress in TM3 cells stably expressing mutant myocilin. Interestingly, the topical ocular AS.IV eye drops (1 mM) significantly decreased TGFβ2 induced ocular hypertension in mice, and this was associated with a decrease in FN, Col-1 (ECM), KDEL (ER stress) and αSMA in mouse TM tissues. Taken together, the results suggest that AS.IV prevents TGFβ2 induced ocular hypertension by modulating ECM deposition and ER stress in the TM.Ramesh B. KasettiPrabhavathi MaddineniBindu KodatiBhavani NagarajanSam YacoubMDPI AGarticleastragaloside IVtrabecular meshworkTGFβ2myocilinECMMMPBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12508, p 12508 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	astragaloside IV trabecular meshwork TGFβ2 myocilin ECM MMP Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	astragaloside IV trabecular meshwork TGFβ2 myocilin ECM MMP Biology (General) QH301-705.5 Chemistry QD1-999 Ramesh B. Kasetti Prabhavathi Maddineni Bindu Kodati Bhavani Nagarajan Sam Yacoub Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
description	Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular matrix (ECM) production, deposition and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) contribute to increased aqueous humor (AH) outflow resistance and IOP elevation. Drugs which alter the glaucomatous fibrotic changes and ER stress in the TM may be effective in reducing ocular hypertension. Astragaloside IV (AS.IV), a novel saponin isolated from the roots of <i>Astragalus membranaceus</i>, has demonstrated antifibrotic and ER stress lowering effects in various tissues during disease conditions. However, the effect of AS.IV on glaucomatous TM fibrosis, ER stress and ocular hypertension has not been studied. Primary human TM cells treated with AS.IV decreased TGFβ2 induced ECM (FN, Col-I) deposition and ER stress (KDEL, ATF4 and CHOP). Moreover, AS.IV treatment reduced TGFβ2 induced NF-κB activation and αSMA expression in TM cells. We found that AS.IV treatment significantly increased levels of matrix metalloproteases (MMP9 and MMP2) and MMP2 enzymatic activity, indicating that the antifibrotic effects of AS.IV are mediated via inhibition of NF-κB and activation of MMPs. AS.IV treatment also reduced ER stress in TM3 cells stably expressing mutant myocilin. Interestingly, the topical ocular AS.IV eye drops (1 mM) significantly decreased TGFβ2 induced ocular hypertension in mice, and this was associated with a decrease in FN, Col-1 (ECM), KDEL (ER stress) and αSMA in mouse TM tissues. Taken together, the results suggest that AS.IV prevents TGFβ2 induced ocular hypertension by modulating ECM deposition and ER stress in the TM.
format	article
author	Ramesh B. Kasetti Prabhavathi Maddineni Bindu Kodati Bhavani Nagarajan Sam Yacoub
author_facet	Ramesh B. Kasetti Prabhavathi Maddineni Bindu Kodati Bhavani Nagarajan Sam Yacoub
author_sort	Ramesh B. Kasetti
title	Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
title_short	Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
title_full	Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
title_fullStr	Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
title_full_unstemmed	Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
title_sort	astragaloside iv attenuates ocular hypertension in a mouse model of tgfβ2 induced primary open angle glaucoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/90f5095072a24a44916bcf28d17786b3
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Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma

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