The North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA.
Sci Rep. 2017 Nov 2;7(1):14951. doi: 10.1038/s41598-017-14938-0.
Increased synthesis and deposition of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) is associated with TM dysfunction and intraocular pressure (IOP) elevation in glaucoma. However, it is not understood how ECM accumulation leads to TM dysfunction and IOP elevation. Using a mouse model of glucocorticoid (GC)-induced glaucoma, primary human TM cells and human post-mortem TM tissues, we show that increased ECM accumulation leads to endoplasmic reticulum (ER) stress in the TM. The potent GC, dexamethasone (Dex) increased the secretory protein load of ECM proteins in the ER of TM cells, inducing ER stress. Reduction of fibronectin, a major regulator of ECM structure, prevented ER stress in Dex-treated TM cells. Overexpression of fibronectin via treatment with cellular fibronectin also induced chronic ER stress in primary human TM cells. Primary human TM cells grown on ECM derived from Dex-treated TM cells induced ER stress markers. TM cells were more prone to ER stress from ECM accumulation compared to other ocular cell types. Moreover, increased co-localization of ECM proteins with ER stress markers was observed in human post-mortem glaucomatous TM tissues. These data indicate that ER stress is associated with increased ECM accumulation in mouse and human glaucomatous TM tissues.
细胞外基质（ECM）蛋白在小梁网（TM）中的合成和沉积增加与 TM 功能障碍和青光眼的眼内压（IOP）升高有关。然而，尚不清楚 ECM 积累如何导致 TM 功能障碍和 IOP 升高。本研究使用糖皮质激素（GC）诱导的青光眼小鼠模型、原代人 TM 细胞和人死后 TM 组织，表明 ECM 积累导致 TM 中的内质网（ER）应激。强效 GC，地塞米松（Dex）增加了 TM 细胞 ER 中 ECM 蛋白的分泌蛋白负荷，诱导 ER 应激。纤连蛋白（一种 ECM 结构的主要调节剂）的减少可防止 Dex 处理的 TM 细胞中的 ER 应激。通过用细胞纤连蛋白处理过表达纤连蛋白也会在原代人 TM 细胞中诱导慢性 ER 应激。在源自 Dex 处理的 TM 细胞的 ECM 上生长的原代人 TM 细胞诱导 ER 应激标志物。与其他眼细胞类型相比，TM 细胞更容易受到 ECM 积累引起的 ER 应激。此外，在人死后的青光眼 TM 组织中观察到 ECM 蛋白与 ER 应激标志物的共定位增加。这些数据表明，ER 应激与小鼠和人青光眼 TM 组织中 ECM 积累的增加有关。
