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Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork

This study provides comprehensive mechanistic evidence for the role of clusterin, a stress‐response secretory chaperone protein, in the modulation of intraocular pressure (IOP) by regulating the trabecular meshwork (TM) actin cytoskeleton and the extracellular matrix (ECM). The pathological stressor...

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Autores principales: Soundararajan, Avinash, Wang, Ting, Ghag, Sachin A., Kang, Min H., Pattabiraman, Padmanabhan P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283260/
https://www.ncbi.nlm.nih.gov/pubmed/35567755
http://dx.doi.org/10.1002/jcp.30769
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author Soundararajan, Avinash
Wang, Ting
Ghag, Sachin A.
Kang, Min H.
Pattabiraman, Padmanabhan P.
author_facet Soundararajan, Avinash
Wang, Ting
Ghag, Sachin A.
Kang, Min H.
Pattabiraman, Padmanabhan P.
author_sort Soundararajan, Avinash
collection PubMed
description This study provides comprehensive mechanistic evidence for the role of clusterin, a stress‐response secretory chaperone protein, in the modulation of intraocular pressure (IOP) by regulating the trabecular meshwork (TM) actin cytoskeleton and the extracellular matrix (ECM). The pathological stressors on TM known to elevate IOP significantly lowered clusterin protein levels indicating stress‐related clusterin function loss. Small interfering RNA‐mediated clusterin loss in human TM cells in vitro induced actin polymerization and stabilization via protein kinase D1, serine/threonine‐protein kinase N2 (PRK2), and LIM kinase 1 (LIMK1), and the recruitment and activation of adhesome proteins including paxillin, vinculin, and integrin αV and β5. A complete loss of clusterin as seen in clusterin knockout mice (Clu ( ‐/‐ )) led to significant IOP elevation at postnatal Day 70. Contrarily, constitutive clusterin expression using adenovirus (AdCLU) in HTM cells resulted in the loss of actin polymerization via decreased PRK2, and LIMK1 and negative regulation of integrin αV and β5. Furthermore, we found that AdCLU treatment in HTM cells significantly decreased the ECM protein expression and distribution by significantly increasing matrix metalloprotease 2 (MMP2) activity and lowering the levels of pro‐fibrotic proteins such as transforming growth factor‐β2 (TGFβ2), thrombospondin‐1 (TSP‐1), and plasminogen activator inhibitor‐1 (PAI‐1). Finally, we found that HTM cells supplemented with recombinant human clusterin attenuated the pro‐fibrotic effects of TGFβ2. For the first time this study demonstrates the importance of clusterin in the regulation of TM actin cytoskeleton ‐ ECM interactions and the maintenance of IOP, thus making clusterin an interesting target to reverse elevated IOP.
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spelling pubmed-92832602022-10-14 Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork Soundararajan, Avinash Wang, Ting Ghag, Sachin A. Kang, Min H. Pattabiraman, Padmanabhan P. J Cell Physiol Research Articles This study provides comprehensive mechanistic evidence for the role of clusterin, a stress‐response secretory chaperone protein, in the modulation of intraocular pressure (IOP) by regulating the trabecular meshwork (TM) actin cytoskeleton and the extracellular matrix (ECM). The pathological stressors on TM known to elevate IOP significantly lowered clusterin protein levels indicating stress‐related clusterin function loss. Small interfering RNA‐mediated clusterin loss in human TM cells in vitro induced actin polymerization and stabilization via protein kinase D1, serine/threonine‐protein kinase N2 (PRK2), and LIM kinase 1 (LIMK1), and the recruitment and activation of adhesome proteins including paxillin, vinculin, and integrin αV and β5. A complete loss of clusterin as seen in clusterin knockout mice (Clu ( ‐/‐ )) led to significant IOP elevation at postnatal Day 70. Contrarily, constitutive clusterin expression using adenovirus (AdCLU) in HTM cells resulted in the loss of actin polymerization via decreased PRK2, and LIMK1 and negative regulation of integrin αV and β5. Furthermore, we found that AdCLU treatment in HTM cells significantly decreased the ECM protein expression and distribution by significantly increasing matrix metalloprotease 2 (MMP2) activity and lowering the levels of pro‐fibrotic proteins such as transforming growth factor‐β2 (TGFβ2), thrombospondin‐1 (TSP‐1), and plasminogen activator inhibitor‐1 (PAI‐1). Finally, we found that HTM cells supplemented with recombinant human clusterin attenuated the pro‐fibrotic effects of TGFβ2. For the first time this study demonstrates the importance of clusterin in the regulation of TM actin cytoskeleton ‐ ECM interactions and the maintenance of IOP, thus making clusterin an interesting target to reverse elevated IOP. John Wiley and Sons Inc. 2022-05-14 2022-07 /pmc/articles/PMC9283260/ /pubmed/35567755 http://dx.doi.org/10.1002/jcp.30769 Text en © 2022 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Soundararajan, Avinash
Wang, Ting
Ghag, Sachin A.
Kang, Min H.
Pattabiraman, Padmanabhan P.
Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
title Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
title_full Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
title_fullStr Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
title_full_unstemmed Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
title_short Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
title_sort novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283260/
https://www.ncbi.nlm.nih.gov/pubmed/35567755
http://dx.doi.org/10.1002/jcp.30769
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