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

Autor: Soundararajan A; Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA., Wang T; Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neuroscience Research Institute, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA., Ghag SA; Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA., Kang MH; Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Pattabiraman PP; Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neuroscience Research Institute, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA.
Jazyk: angličtina
Zdroj: Journal of cellular physiology [J Cell Physiol] 2022 Jul; Vol. 237 (7), pp. 3012-3029. Date of Electronic Publication: 2022 May 14.
DOI: 10.1002/jcp.30769
Abstrakt: 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.
(© 2022 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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