Zhiwei Zha, Juan Li, Shuang Xie, Xunjie Shang, Zixin Xu, Haiyuan Chang, Kaisheng Wang, Yang Liu, Wei Chen
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引用次数: 0
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.
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.