Abstract：
Diabetic retinopathy (DR) is the leading cause of vision loss and blindness among working-age adults. Pericyte loss is an early pathological feature of DR. Under hyperglycemic conditions, reactive oxygen species (ROS) production increases, leading to oxidative stress and subsequent mitochondrial dysfunction and apoptosis. Dysfunctional pericyte can cause retinal vascular leakage, obliteration, and neovascularization. Glutaredoxin 2 (Grx2) is a mitochondrial glutathione-dependent oxidoreductase which protects cells against oxidative insults by safeguarding mitochondrial function. Whether Grx2 plays a protective role in diabetes-induced microvascular dysfunction remains unclear. Our findings revealed that diabetes-related stress reduced Grx2 expression in pericytes, but not in endothelial cells. Grx2 knock-in ameliorated diabetes-induced microvascular dysfunction in vivo DR models. Decreased Grx2 expression led to significant pericyte apoptosis, and pericyte dysfunction, namely reduced pericyte recruitment towards endothelial cells and increased endothelial cell permeability. Conversely, upregulating Grx2 reversed these effects. Furthermore, Grx2 regulated pericyte apoptosis by modulating complex I activity, which is crucial for pericyte mitochondrial function. Overall, our study uncovered a novel mechanism whereby high glucose inhibited Grx2 expression in vivo and in vitro. Grx2 downregulation exacerbated pericyte apoptosis, pericyte dysfunction, and retinal vascular dysfunction by inactivating complex I and mediating mitochondrial dysfunction in pericytes.
摘要：
糖尿病视网膜病变（DR）是工作年龄成年人视力丧失和失明的主要原因。周细胞丢失是DR的早期病理特征。在高血糖条件下，活性氧（ROS）产量增加，导致氧化应激和随后的线粒体功能障碍和凋亡。功能失调的周细胞会导致视网膜血管渗漏,抹杀，和新血管形成。谷氧还蛋白2（Grx2）是一种线粒体谷胱甘肽依赖性氧化还原酶，通过保护线粒体功能来保护细胞免受氧化损伤。Grx2是否在糖尿病诱导的微血管功能障碍中起保护作用尚不清楚。我们的发现表明，糖尿病相关的应激降低了周细胞中Grx2的表达，但不在内皮细胞中。Grx2敲入改善体内DR模型中糖尿病诱导的微血管功能障碍。Grx2表达降低导致显著的周细胞凋亡,周细胞功能障碍,即减少周细胞对内皮细胞的募集和增加内皮细胞通透性。相反，上调Grx2逆转了这些效果。此外，Grx2通过调节复合物I活性调节周细胞凋亡,这对周细胞线粒体功能至关重要。总的来说,我们的研究揭示了一种新的机制，即高葡萄糖在体内和体外抑制Grx2表达。Grx2下调加剧了周细胞凋亡，周细胞功能障碍,和视网膜血管功能障碍通过灭活复合物I和介导周细胞线粒体功能障碍。
