Intracellular Zn2+ Promotes Extracellular Matrix Remodeling in Dexamethasone-Treated Trabecular Meshwork

Given 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, providing a novel perspective on the pathogenesis of glaucoma.

鉴于糖皮质激素（glucocorticoids）在眼科领域的广泛应用，其引发的眼压（intraocular pressure，IOP）升高长期以来一直是临床医师面临的棘手难题，但其具体发病机制至今尚未明确。目前学界的研究焦点多集中于小梁网（trabecular meshwork，TM）的细胞外基质（extracellular matrix，ECM）。学界普遍认为，糖皮质激素会影响基质金属蛋白酶（matrix metalloproteinases，MMPs）的表达，进而导致细胞外基质沉积。鉴于锌离子（Zn²+）对基质金属蛋白酶具有关键作用，本研究探讨了其在地塞米松（dexamethasone，DEX）诱导的细胞外基质改变中的作用。本研究结果显示，在地塞米松处理的人小梁网细胞中，细胞内锌离子水平显著降低，同时细胞外锌离子摄取能力受损。这一现象与多种Zrt/Irt相关蛋白（Zrt-, Irt-related proteins，ZIP）及金属硫蛋白（metallothionein）的表达变化相关。敲低ZIP8会削弱细胞外锌离子的摄取能力，但锌离子螯合并不影响ZIP8的表达。与地塞米松的作用类似，锌离子螯合会降低MMP2的表达、增加细胞外基质蛋白沉积，并引发细胞外基质结构紊乱。相反，向经地塞米松处理的细胞外源性补充锌离子，可改善上述异常表型。令人振奋的是，在小鼠中通过饮食补充锌离子，可显著降低地塞米松诱导的眼压升高及小梁网胶原含量，进而挽救小鼠的视觉功能。本研究结果明确了锌离子在细胞外基质调控中的关键作用，为青光眼的发病机制研究提供了全新视角。