FGF10 Protects the Corneal Epithelium From Dry Eye-Induced Oxidative and ER Stress Via Upregulation of SLC7A11.

IF 5 2区 医学 Q1 OPHTHALMOLOGY
Zhiwei Zha, Juan Li, Shuang Xie, Xunjie Shang, Zixin Xu, Haiyuan Chang, Kaisheng Wang, Yang Liu, Wei Chen
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Abstract

Purpose: To investigate the protective effect of fibroblast growth factor 10 (FGF10) on the corneal epithelium in dry eye disease (DED) and reveal the underlying mechanism.

Methods: DED mouse model was induced via scopolamine injections and low-humidity airflow to evaluate the therapeutic effects of FGF10. Mice received topical FGF10 (5, 25, or 125 µg/mL) or vehicle for seven days. Corneal fluorescein staining, oxidative stress (ROS levels), endoplasmic reticulum (ER) stress, and apoptosis were evaluated. To investigate protective mechanisms on corneal epithelium cells, hyperosmolar-stressed HCE-2 cells were treated with 100 ng/mL FGF10, and RNA sequencing was performed. Transcriptomic analysis identified SLC7A11, a key regulator of cellular antioxidant defense, as significantly upregulated by FGF10. SLC7A11's functional importance was validated through siRNA-mediated silencing in HCE-2 cells and AAV-mediated overexpression in mouse model.

Results: FGF10 treatment significantly improved corneal epithelial integrity in dry eye mice, reducing fluorescein staining, ROS level, and ER stress markers, while increasing Bcl-2 and decreasing BAX. RNA sequencing revealed that FGF10 stimulated antioxidant signaling pathways and upregulated SLC7A11 expression. FGF10 also increased SLC7A11 protein levels in HCE-2 cells and dry eye corneas. Silencing of SLC7A11 in vitro prevented FGF10-induced reductions in ROS, ER stress, and apoptosis. Furthermore, AAV-mediated overexpression of SLC7A11 in dry eye mice recapitulated the protective effects observed with FGF10 treatment.

Conclusions: FGF10 protects mouse corneal epithelium and HCE-2 cells from oxidative stress, ER stress, and apoptosis, partially through SLC7A11 upregulation. The FGF10-SLC7A11 pathway represents a promising therapeutic target in dry eye.

FGF10通过上调SLC7A11保护干眼诱导的角膜上皮氧化应激和内质网应激。
目的:探讨成纤维细胞生长因子10 (FGF10)对干眼病(DED)角膜上皮的保护作用及其机制。方法:采用东莨菪碱注射和低湿度气流诱导小鼠DED模型,评价FGF10的治疗作用。小鼠外用FGF10(5、25或125µg/mL)或对照物7天。评估角膜荧光素染色、氧化应激(ROS)水平、内质网应激(ER)和细胞凋亡。为了研究对角膜上皮细胞的保护机制,我们用100 ng/mL FGF10处理高渗应激的HCE-2细胞,并进行RNA测序。转录组学分析发现,FGF10显著上调了细胞抗氧化防御的关键调节因子SLC7A11。通过sirna介导的HCE-2细胞沉默和aav介导的小鼠模型过表达,验证了SLC7A11的功能重要性。结果:FGF10处理显著改善了干眼小鼠角膜上皮的完整性,降低了荧光素染色、ROS水平和内质网应激标志物,同时增加了Bcl-2,降低了BAX。RNA测序显示,FGF10刺激抗氧化信号通路,上调SLC7A11的表达。FGF10还增加了HCE-2细胞和干眼角膜中的SLC7A11蛋白水平。体外沉默SLC7A11可阻止fgf10诱导的ROS、内质网应激和细胞凋亡的减少。此外,aav介导的SLC7A11在干眼小鼠中的过表达重现了FGF10治疗所观察到的保护作用。结论:FGF10保护小鼠角膜上皮和HCE-2细胞免受氧化应激、内质网应激和凋亡,其部分机制是通过上调SLC7A11实现的。FGF10-SLC7A11通路是干眼症的一个有前景的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.90
自引率
4.50%
发文量
339
审稿时长
1 months
期刊介绍: Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.
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