Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, 75006, Paris, France.
Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, 75006, Paris, France.
Nat Commun. 2019 Jan 21;10(1):369. doi: 10.1038/s41467-018-08125-6.
Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin. Intravitreal injections of spironolactone-loaded microspheres and systemic delivery lead to similar reductions in CNV. Together, our work suggests MR inhibition as a novel therapeutic option for wet AMD patients unresponsive to anti-VEGF drugs.
脉络膜新生血管（CNV）是湿性年龄相关性黄斑变性（AMD）患者视力损害的主要原因，特别是在对眼内抗血管内皮生长因子（VEGF）注射治疗产生抗药性时。在这里，我们报告称，口服盐皮质激素受体（MR）拮抗剂螺内酯治疗可减轻对抗 VEGF 治疗产生抗药性的患者的 CNV 迹象。在湿性 AMD 的动物模型中，MR 途径的药理学抑制或内皮细胞特异性 MR 缺失通过非 VEGF 依赖机制抑制 CNV，部分是通过上调细胞外基质蛋白 decorin。玻璃体内注射螺内酯负载的微球和全身给药可导致 CNV 类似减少。总之，我们的工作表明，MR 抑制作为一种新的治疗选择，可用于对抗 VEGF 药物无反应的湿性 AMD 患者。
