Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion
Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion
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DOI：
10.3390/ijms20163969
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发表时间：
2019-08-02
影响因子：
5.6
通讯作者：
El-Remessy, Azza B.
中科院分区：
文献类型：
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作者：
Coucha, Maha;Shanab, Ahmed Y.;El-Remessy, Azza B.
视网膜神经变性是几种致盲性疾病的早期特征，其触发神经胶质活化，导致炎症、继发性损伤和视力损害。仅针对神经保护的治疗在临床上失败了。在此，我们研究了在缺血/再灌注（IR）模型中调节硫氧还蛋白相互作用蛋白（TXNIP）对炎症继发性损伤和视觉损害的影响。野生型（WT）和TXNIP敲除（TKO）小鼠通过增加眼内压40分钟经历IR损伤，随后再灌注。另一组WT小鼠在IR损伤后2天接受玻璃体内TXNIP-反义寡聚物（ASO，100 μ g/2 μ L）。评估Muller胶质细胞的活化、细胞凋亡和炎性体标志物的表达以及视觉功能。与假手术对照组相比，IR损伤触发了持续14天的早期TXNIP mRNA表达，并定位于WT-IR中活化的Muller细胞内。暴露于缺氧-复氧损伤的Muller细胞在WT细胞中触发内质网（ER）应激标志物和炎性小体激活，但TKO细胞中没有。继发性损伤是明显的，在IR-WT小鼠中闭塞的无细胞毛细血管的数量显著增加和视觉障碍，但在IR-TKO中没有。与未处理的WT相比，TXNIP-ASO干预预防了缺血诱导的胶质细胞活化和神经血管变性，并改善了视觉功能。靶向TXNIP表达可能为预防与视网膜神经退行性疾病相关的继发性损伤提供有效方法。
Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 mu g/2 mu L) 2 days post IR injury. Activation of Muller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Muller cells in WT-IR, compared to sham controls. Exposure of Muller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.