Intracellular Zn < sup > 2+ < /sup > Promotes Extracellular Matrix Remodeling in Dexamethasone-Treated Trabecular Meshwork

Am J Physiol Cell Physiol. 2024 Mar 25. doi: 10.1152/ajpcell.00725.2023. Online ahead of print.ABSTRACTGiven the widespread application of glucocorticoids in ophthalmology, the associated elevation of intraocular pressure (IOP) has long been a vexing concern for clinicians, yet the underlying mechanisms remain inconclusive. Much of the discussion focuses on the extracellular matrix (ECM) of trabecular meshwork (TM). It's widely agreed that glucocorticoids impact the expression of Matrix metalloproteinases (MMPs), leading to ECM deposition. Since Zn2+ is vital for MMPs, we explored its role in ECM alterations induced by dexamethasone (DEX). Our study revealed that in human TM cells treated with DEX, the level of intracellular Zn2+ significantly decreased and accompanied by impaired extracellular Zn2+ uptake. This correlated with changes in several Zrt-, Irt-related proteins (ZIP) and metallothionein. ZIP8 knockdown impaired extracellular Zn2+ uptake, but Zn2+ chelation didn't affect ZIP8 expression. Resembling DEX's effects, chelating Zn2+ decreased MMP2 expression, increased the deposition of ECM proteins, and induced structural disarray of ECM. Conversely, supplementation of exogenous Zn2+ to DEX-treated cells ameliorated these outcomes. Inspiringly, dietary zinc supplementation in mice significantly reduced DEX-induced IOP elevation and collagen content in TM, thereby rescuing the visual function of the mice. These findings underscore zinc's pivotal role in ECM regulation, ...
Source: Am J Physiol Cell Ph... - Category: Cytology Authors: Source Type: research