State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Exp Eye Res. 2022 Aug;221:109142. doi: 10.1016/j.exer.2022.109142. Epub 2022 Jun 10.
Diabetic retinopathy (DR) is one of the most common blindness in working-age adults. Transcription factor 7 like 2 (TCF7L2) is a susceptibility gene of DR, however, its roles in the pathogenesis of DR are still largely unknown. In this study, we found that TCF7L2 was mainly located in the cell nucleus of retinal ganglion cell layer (GCL) and inner nuclear layer (INL), while it was not expressed in the cell nucleus of retinal outer nuclear layer (ONL). Expression of TCF7L2 was significantly elevated in the retinas of db/db diabetic mice and oxygen-induced retinopathy (OIR) mice. Also, in Ad-hTCF7L2 treated hiPSCs-derived retinal progenitor cells (RPCs), activating transcription factor 6 (ATF6)-related endoplasmic reticulum (ER) stress signaling was remarkably activated. Moreover, knockdown of TCF7L2 significantly inhibited ATF6-related ER stress signaling. Furthermore, the data of endothelial permeability assay showed that RPCs pretreated with Ad-hTCF7L2 lead to enhanced monolayer permeability of human umbilical vein endothelial cells (HUVECs), and knockdown of TCF7L2 or ATF6 in RPCs could alleviate the monolayer permeability of HUVECs. Thus, our results showed that TCF7L2 could trigger ATF6-related ER stress signaling and promote vein endothelial cell permeability, which will provide important insight into the role of TCF7L2 in the pathogenesis of DR and contribute to designing potential therapies.
糖尿病性视网膜病变 (DR) 是工作年龄成年人中最常见的致盲眼病之一。转录因子 7 样 2 (TCF7L2) 是 DR 的易感基因，然而，其在 DR 发病机制中的作用仍知之甚少。在本研究中，我们发现 TCF7L2 主要位于视网膜神经节细胞层 (GCL) 和内核层 (INL) 的细胞核内，而在外核层 (ONL) 的细胞核内不表达。db/db 糖尿病小鼠和氧诱导视网膜病变 (OIR) 小鼠的视网膜中 TCF7L2 的表达显著升高。此外，在 Ad-hTCF7L2 处理的 hiPSC 衍生的视网膜祖细胞 (RPCs) 中，激活转录因子 6 (ATF6) 相关的内质网 (ER) 应激信号显著激活。此外，TCF7L2 的敲低显著抑制了 ATF6 相关的 ER 应激信号。此外，内皮通透性测定结果表明，经 Ad-hTCF7L2 预处理的 RPCs 导致人脐静脉内皮细胞 (HUVECs) 的单层通透性增强，而 RPCs 中 TCF7L2 或 ATF6 的敲低可减轻 HUVECs 的单层通透性。因此，我们的结果表明 TCF7L2 可触发 ATF6 相关的 ER 应激信号，并促进静脉内皮细胞通透性，这将为 TCF7L2 在 DR 发病机制中的作用提供重要的见解，并有助于设计潜在的治疗方法。
