糖尿病性视网膜病变
缺氧诱导因子
视网膜
缺氧(环境)
视网膜
血管内皮生长因子
发病机制
医学
视网膜病变
新生血管
内分泌学
药理学
糖尿病
内科学
生物
血管生成
化学
眼科
血管内皮生长因子受体
生物化学
神经科学
氧气
有机化学
基因
作者
Jing Zhang,Deepti Sharma,Aumreetam Dinabandhu,Jaron Castillo Sanchez,Brooks P. Applewhite,Kathleen Jee,Monika Deshpande,Miguel Flores-Bellver,Ming-Wen Hu,Chuanyu Guo,Shaima Salman,Yousang Hwang,Nicole M. Anders,Michelle A. Rudek,Jiang Qian,M. Valeria Canto‐Soler,Gregg L. Semenza,Silvia Montaner,Akrit Sodhi
摘要
Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by hypoxia-inducible factor (HIF)-1 and -2 (HIFs) remain elevated in diabetic eyes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF-inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.
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