Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Biomedical Research, Gifu Pharmaceutical University, Gifu, Japan.
Invest Ophthalmol Vis Sci. 2019 May 1;60(6):1943-1952. doi: 10.1167/iovs.18-25745.
Ocular angiogenesis, including retinopathy of prematurity, diabetic retinopathy, and exudative age-related macular degeneration, are closely related to oxidative stress. Many reports have shown that the cellular protective mechanism against oxidative stress and inflammatory response has nuclear factor-erythroid 2-related factor-2 (Nrf2) activity. The aim of this study was to investigate the effectiveness and mechanism of Nrf2 activation in treating the ocular diseases with abnormal vessels.
The effects of Nrf2 activators, bardoxolone methyl (BARD) and RS9, were evaluated against vascular endothelial growth factor (VEGF)-induced cell migration in human retinal microvascular endothelial cells (HRMECs). We measured the expression of the Nrf2 target genes, Ho-1 and Nqo-1 mRNA, in mouse retinas after a single injection of BARD and RS9. The effects and mechanisms of RS9 against retinal angiogenesis were evaluated using an oxygen-induced retinopathy (OIR) model in mice. Moreover, the effect of RS9 against choroidal neovascularization (CNV) was evaluated in a laser-induced CNV monkey model.
Both BARD and RS9 decreased VEGF-induced cell migration, and significantly increased Ho-1 mRNA expression; however, only RS9 significantly increased Nqo-1 mRNA. RS9 decreased retinal neovascularization through suppressing VEGF expression and increasing Nrf2, HO-1, platelet-derived growth factor receptor (PDGFR)-β, and tight junction proteins in OIR murine retinas. Furthermore, RS9 showed a tendency toward decreasing CNV lesions, and improved vascular leakage in a CNV monkey model.
These data indicate that a Nrf2 activator might be a candidate for treatment of ocular diseases characterized by pathophysiological angiogenesis and hyperpermeability.
眼部血管生成，包括早产儿视网膜病变、糖尿病视网膜病变和渗出性年龄相关性黄斑变性，与氧化应激密切相关。许多报道表明，细胞对抗氧化应激和炎症反应的保护机制与核因子-红细胞 2 相关因子 2（Nrf2）活性有关。本研究旨在探讨 Nrf2 激活在治疗异常血管性眼病中的有效性和机制。
评估 Nrf2 激活剂 bardoxolone 甲基（BARD）和 RS9 对人视网膜微血管内皮细胞（HRMEC）中血管内皮生长因子（VEGF）诱导的细胞迁移的影响。我们测量了 BARD 和 RS9 单次注射后小鼠视网膜中 Nrf2 靶基因 Ho-1 和 Nqo-1mRNA 的表达。在小鼠氧诱导视网膜病变（OIR）模型中评估 RS9 对视网膜血管生成的作用和机制。此外，在激光诱导的脉络膜新生血管（CNV）猴模型中评估了 RS9 对脉络膜新生血管（CNV）的作用。
BARD 和 RS9 均降低了 VEGF 诱导的细胞迁移，并显著增加了 Ho-1mRNA 的表达；然而，只有 RS9 显著增加了 Nqo-1mRNA。RS9 通过抑制 VEGF 表达和增加 OIR 小鼠视网膜中的 Nrf2、HO-1、血小板衍生生长因子受体（PDGFR）-β 和紧密连接蛋白来减少视网膜新生血管形成。此外，RS9 在 CNV 猴模型中显示出减少 CNV 病变和改善血管渗漏的趋势。
这些数据表明，Nrf2 激活剂可能是治疗以病理生理血管生成和高通透性为特征的眼部疾病的候选药物。
