Abstract：
Glucocorticoid use may cause elevated intraocular pressure, leading to the development of glucocorticoid-induced glaucoma (GIG). However, the mechanism of GIG development remains incompletely understood. In this study, we subjected primary human trabecular meshwork cells (TMCs) and mice to dexamethasone treatment to mimic glucocorticoid exposure. The myofibroblast transdifferentiation of TMCs was observed in cellular and mouse models, as well as in human trabecular mesh specimens. This was demonstrated by the cytoskeletal reorganization, alterations in cell morphology, heightened transdifferentiation markers, increased extracellular matrix deposition, and cellular dysfunction. Knockdown of Rho guanine nucleotide exchange factor 26 (ARHGEF26) expression ameliorated dexamethasone-induced changes in cell morphology and upregulation of myofibroblast markers, reversed dysfunction and extracellular matrix deposition in TMCs, and prevented the development of dexamethasone-induced intraocular hypertension. And, this process may be related to the TGF-β pathway. In conclusion, glucocorticoids induced the myofibroblast transdifferentiation in TMCs, which played a crucial role in the pathogenesis of GIG. Inhibition of ARHGEF26 expression protected TMCs by reversing myofibroblast transdifferentiation. This study demonstrated the potential of reversing the myofibroblast transdifferentiation of TMCs as a new target for treating GIG.
摘要：
使用糖皮质激素可能会导致眼内压升高，导致糖皮质激素诱导的青光眼（GIG）的发展。然而,GIG发展的机制尚不完全清楚。在这项研究中,我们对原代人小梁细胞(TMCs)和小鼠进行地塞米松处理以模拟糖皮质激素暴露.在细胞和小鼠模型中观察到TMC的肌成纤维细胞转分化，以及人体小梁网格标本。细胞骨架重组证明了这一点，细胞形态的改变，增强的转分化标记，细胞外基质沉积增加，和细胞功能障碍。敲除Rho鸟嘌呤核苷酸交换因子26（ARHGEF26）表达改善了地塞米松诱导的细胞形态变化和肌成纤维细胞标志物的上调，TMC中的逆转功能障碍和细胞外基质沉积，并阻止地塞米松诱导的高眼压的发展。And,这一过程可能与TGF-β途径有关。总之,糖皮质激素诱导TMC中的肌成纤维细胞转分化，在GIG的发病机制中起着至关重要的作用。ARHGEF26表达的抑制通过逆转成肌纤维细胞转分化来保护TMCs。这项研究证明了逆转TMC的成肌纤维细胞转分化作为治疗GIG的新靶标的潜力。
