Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
J Diabetes Investig. 2019 Jan;10(1):6-17. doi: 10.1111/jdi.12842. Epub 2018 May 13.
The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis.
肾素-血管紧张素系统（RAS）是系统血压（循环 RAS）的关键调节剂，在各种器官的病理性血管生成和炎症中发挥独特的作用，如糖尿病微血管并发症。我们使用眼部临床样本和动物疾病模型，阐明了组织 RAS 激发血管内皮生长因子（VEGF-A）表达的分子机制，VEGF-A 是糖尿病视网膜病变（DR）中视网膜炎症和血管生成的两个主要病理事件的关键因素。此外，我们还表明（前）肾素受体[（P）RR]参与了视网膜 RAS 的激活及其伴随的细胞内信号转导（如细胞外信号调节激酶）；即，（P）RR 诱导的双重致病生物活性，称为受体相关前肾素系统。事实上，来自增殖性 DR 眼的纤维血管组织中的新生血管内皮细胞对受体相关前肾素系统成分（包括前肾素、（P）RR、磷酸化细胞外信号调节激酶和 VEGF-A）呈免疫反应性。可溶（P）RR 的蛋白水平随其与前肾素、肾素酶活性和增殖性 DR 眼中玻璃体内 VEGF 的正相关而增加，表明（P）RR 与 VEGF-A 驱动的血管生成活性之间存在密切联系。此外，我们揭示了（P）RR 在葡萄糖诱导的氧化应激中一个意想不到的、与 PAPS 无关的作用。最近，我们开发了一种创新的单链核糖核酸干扰分子，该分子选择性靶向人和小鼠（P）RR，并证实了其在抑制糖尿病诱导的小鼠视网膜炎症中的功效。我们使用临床样本和动物模型的数据表明（P）RR 在 DR 发病机制中的重要意义，以及核糖核酸干扰分子作为一种治疗剂来减轻眼部炎症和血管生成的潜在用途。
