Department of Medicine, Washington University, St. Louis, Missouri, USA.
National Institute of Health, Bethesda, Maryland, USA.
Sci Rep. 2018 Feb 14;8(1):3025. doi: 10.1038/s41598-018-21276-2.
Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Increased iron accumulation is associated with several degenerative diseases. However, there are no reports on the status of retinal iron or its implications in the pathogenesis of DR. In the present study, we found that retinas of type-1 and type-2 mouse models of diabetes have increased iron accumulation compared to non-diabetic retinas. We found similar iron accumulation in postmortem retinal samples from human diabetic patients. Further, we induced diabetes in HFE knockout (KO) mice model of genetic iron overload to understand the role of iron in the pathogenesis of DR. We found increased neuronal cell death, vascular alterations and loss of retinal barrier integrity in diabetic HFE KO mice compared to diabetic wildtype mice. Diabetic HFE KO mouse retinas also exhibited increased expression of inflammation and oxidative stress markers. Severity in the pathogenesis of DR in HFE KO mice was accompanied by increase in retinal renin expression mediated by G-protein-coupled succinate receptor GPR91. In light of previous reports implicating retinal renin-angiotensin system in DR pathogenesis, our results reveal a novel relationship between diabetes, iron and renin-angiotensin system, thereby unraveling new therapeutic targets for the treatment of DR.
糖尿病性视网膜病变 (DR) 是导致工作年龄成年人失明的主要原因。铁积累增加与几种退行性疾病有关。然而，目前还没有关于视网膜铁的状态或其在 DR 发病机制中的意义的报道。在本研究中，我们发现 1 型和 2 型糖尿病小鼠模型的视网膜与非糖尿病视网膜相比铁积累增加。我们在来自糖尿病患者的死后视网膜样本中发现了类似的铁积累。此外，我们在遗传性铁过载的 HFE 敲除 (KO) 小鼠模型中诱导糖尿病，以了解铁在 DR 发病机制中的作用。与糖尿病野生型小鼠相比，糖尿病 HFE KO 小鼠的神经元细胞死亡、血管改变和视网膜屏障完整性丧失增加。与糖尿病野生型小鼠相比，HFE KO 小鼠糖尿病的发病机制严重程度伴随着视网膜肾素表达的增加，这是由 G 蛋白偶联琥珀酸受体 GPR91 介导的。鉴于先前有研究表明视网膜肾素-血管紧张素系统与 DR 的发病机制有关，我们的结果揭示了糖尿病、铁和肾素-血管紧张素系统之间的新关系，从而为 DR 的治疗提供了新的治疗靶点。
