Eye Center of Xiangya Hospital, Central South University, Changsha, P.R. China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, P.R. China.
FASEB J. 2022 Oct;36(10):e22531. doi: 10.1096/fj.202200366RR.
Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and will lead to visual impairment. We aim to explore the effects and mechanisms of wnt inhibitory factor 1 (WIF1) in the progression of DR. To establish DR in vitro and in vivo, human retinal pigment epithelium (RPE) cell line ARPE-19 was treated with high-glucose (HG) and diabetic mice models were induced by streptozotocin (STZ), respectively. Different dose of recombinant WIF1 protein was used to treat DR. qRT-PCR and western blotting results demonstrated that WIF1 was downregulated, while VEGFA was upregulated in HG-induced ARPE-19 cells. WIF1 overexpression promoted cell migration. The ARPE-19 cells culture medium treated with WIF1 inhibited retinal endothelial cell tube formation and downregulated VEGFA expression. Moreover, WIF1 decreased the levels of ROS and MDA, while increasing the activity of SOD and GPX. WIF1 increased the ΔΨm in the mitochondria and downregulated the expression of mitochondrial autophagy-related proteins including Parkin, Pink1, LC3-II/LC3-I ratio, cleaved caspase 3, and cyt-c, which ameliorated mitochondrial dysfunction. The in vivo studies further demonstrated the consistent effects of WIF1 in STZ-induced mice. Taken together, WIF1 ameliorated mitochondrial dysfunction in DR by downregulating the AMPK/mTOR pathway.
糖尿病性视网膜病变（DR）是糖尿病最常见的并发症之一，会导致视力损害。我们旨在探讨 wnt 抑制因子 1（WIF1）在 DR 进展中的作用和机制。为了在体外和体内建立 DR，分别用人视网膜色素上皮（RPE）细胞系 ARPE-19 进行高糖（HG）处理和链脲佐菌素（STZ）诱导糖尿病小鼠模型。用不同剂量的重组 WIF1 蛋白治疗 DR。qRT-PCR 和 Western blot 结果表明，HG 诱导的 ARPE-19 细胞中 WIF1 下调，而 VEGFA 上调。WIF1 过表达促进细胞迁移。用 WIF1 处理的 ARPE-19 细胞培养基抑制视网膜内皮细胞管形成并下调 VEGFA 表达。此外，WIF1 降低了 ROS 和 MDA 的水平，同时增加了 SOD 和 GPX 的活性。WIF1 增加了线粒体中的ΔΨm，并下调了线粒体自噬相关蛋白的表达，包括 Parkin、Pink1、LC3-II/LC3-I 比值、cleaved caspase 3 和 cyt-c，从而改善了线粒体功能障碍。体内研究进一步证明了 WIF1 在 STZ 诱导的小鼠中的一致作用。总之，WIF1 通过下调 AMPK/mTOR 通路改善了 DR 中的线粒体功能障碍。
