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KLF10-IN-1 Attenuates RPE Cell Apoptosis and Experimental Diabetic Retinopathy Via the KLF10/PERK/eIF2α/ATF4/CHOP
Weiwen Hu1,2, Heng Yang3, Qiqi Zhu2
1Department of Ophthalmology, The First Affiliated Hospital, Jiangxi medical college, Nanchang University, Nanchang, Jiangxi Province, the People's Republic of China.
Purpose:
To investigate the roles of Krüppel-like factor 10 (KLF10) and its inhibitor KLF10-IN-1 in regulating high-glucose/hypoxia-induced RPE cell apoptosis and their involvement in diabetic retinopathy (DR).
Methods:
A DR mouse model was established using a high-fat, high-glucose diet and streptozotocin. An RPE cell model of high-glucose/hypoxia injury was constructed by culturing cells under high-glucose (30 mM) conditions in the presence of cobalt chloride (200 µM). KLF10 expression, apoptosis, and endoplasmic reticulum (ER) stress levels were assessed. KLF10 expression was modulated with small interfering RNA and overexpression plasmids. Dual luciferase reporter assays were used to evaluated the regulatory effect of KLF10 on PERK. The PERK pathway was activated by CCT020312 and inhibited by GSK2606414 for rescue experiments. The protective effects of KLF10-IN-1 were validated in vitro and in vivo.
Results:
KLF10 was highly expressed in RPE cells in DR model mice. After 48 hours of high-glucose/hypoxia exposure, hypoxia, inflammation, ER stress, and apoptosis were significantly exacerbated, accompanied by KLF10 upregulation. KLF10 knockdown suppressed apoptosis and ER stress, whereas KLF10 overexpression had the opposite effect. Western blotting confirmed KLF10 regulated PERK phosphorylation, and dual luciferase assays revealed that KLF10 transcriptionally activates PERK. KLF10 mediated apoptosis through the PERK/eIF2α/ATF4/CHOP pathway. Inhibiting this pathway with KLF10-IN-1 reduced high-glucose/hypoxia-induced damage to RPE cells and ameliorated retinal damage in diabetic mice.
Conclusions:
KLF10 is upregulated in DR model mice and high-glucose/hypoxia-exposed RPE cells and modulates apoptosis and ER stress through the PERK/eIF2α/ATF4/CHOP pathway. KLF10-IN-1 has protective effects, suggesting its potential for early DR treatment.
