Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China.
Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, P. R. China.
Cell Death Dis. 2023 Sep 1;14(9):583. doi: 10.1038/s41419-023-06111-5.
Diabetic retinopathy (DR) is a serious and relatively under-recognized complication of diabetes. Müller glial cells extend throughout the retina and play vital roles in maintaining retinal homeostasis. Previous studies have demonstrated that TGR5, a member of the bile acid-activated GPCR family, could ameliorate DR. However, the role of TGR5 in regulating Müller cell function and the underlying mechanism remains to be ascertained. To address this, high glucose (HG)-treated human Müller cells and streptozotocin-treated Sprague-Dawley rats were used in the study. The IP3R1-GRP75-VDAC1 axis and mitochondrial function were assessed after TGR5 ablation or agonism. Cytosolic mitochondrial DNA (mtDNA)-mediated cGAS-STING activation was performed. The key markers of retinal vascular leakage, apoptosis, and inflammation were examined. We found that mitochondrial Ca overload and mitochondrial dysfunction were alleviated by TGR5 agonist. Mechanically, TGR5 blocked the IP3R1-GRP75-VDAC1 axis mediated Ca efflux from the endoplasmic reticulum into mitochondria under diabetic condition. Mitochondrial Ca overload led to the opening of the mitochondrial permeability transition pore and the release of mitochondrial DNA (mtDNA) into the cytosol. Cytoplasmic mtDNA bound to cGAS and upregulated 2'3' cyclic GMP-AMP. Consequently, STING-mediated inflammatory responses were activated. TGR5 agonist prevented retinal injury, whereas knockdown of TGR5 exacerbated retinal damage in DR rats, which was rescued by the STING inhibitor. Based on the above results, we propose that TGR5 might be a novel therapeutic target for the treatment of DR.
糖尿病性视网膜病变（DR）是糖尿病严重且相对未被认识的并发症。Müller 胶质细胞延伸至整个视网膜，在维持视网膜内环境平衡方面发挥着重要作用。先前的研究表明，TGR5（胆酸激活 G 蛋白偶联受体家族的一员）可以改善 DR。然而，TGR5 在调节 Müller 细胞功能中的作用及其潜在机制仍有待确定。为了解决这个问题，本研究使用了高葡萄糖（HG）处理的人 Müller 细胞和链脲佐菌素处理的 Sprague-Dawley 大鼠。在 TGR5 缺失或激动后评估了 IP3R1-GRP75-VDAC1 轴和线粒体功能。进行了细胞质线粒体 DNA（mtDNA）介导的 cGAS-STING 激活。检查了视网膜血管渗漏、细胞凋亡和炎症的关键标志物。我们发现 TGR5 激动剂减轻了线粒体 Ca 超载和线粒体功能障碍。在糖尿病条件下，TGR5 阻断了 IP3R1-GRP75-VDAC1 轴介导的内质网 Ca 向线粒体流出。线粒体 Ca 超载导致线粒体通透性转换孔打开，线粒体 DNA（mtDNA）释放到细胞质中。细胞质 mtDNA 与 cGAS 结合并上调 2'3' 环鸟苷酸-腺苷酸。因此，STING 介导的炎症反应被激活。TGR5 激动剂可预防视网膜损伤，而 DR 大鼠中 TGR5 的敲低则加剧了视网膜损伤，STING 抑制剂可挽救这种损伤。基于上述结果，我们提出 TGR5 可能是治疗 DR 的一种新的治疗靶点。
