1. Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration.
- Author
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Zhao M, Mantel I, Gelize E, Li X, Xie X, Arboleda A, Seminel M, Levy-Boukris R, Dernigoghossian M, Prunotto A, Andrieu-Soler C, Rivolta C, Canonica J, Naud MC, Lechner S, Farman N, Bravo-Osuna I, Herrero-Vanrell R, Jaisser F, and Behar-Cohen F
- Subjects
- Aged, Aged, 80 and over, Animals, Choroid drug effects, Choroid metabolism, Choroid pathology, Choroidal Neovascularization genetics, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Drug Compounding methods, Female, Gene Expression, Humans, Intravitreal Injections, Macular Degeneration genetics, Macular Degeneration metabolism, Macular Degeneration pathology, Male, Mice, Mice, Transgenic, Microspheres, Pilot Projects, Prospective Studies, Ranibizumab therapeutic use, Rats, Long-Evans, Receptors, Mineralocorticoid metabolism, Receptors, Vascular Endothelial Growth Factor therapeutic use, Recombinant Fusion Proteins therapeutic use, Treatment Outcome, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors therapeutic use, Choroidal Neovascularization drug therapy, Macular Degeneration drug therapy, Mineralocorticoid Receptor Antagonists therapeutic use, Receptors, Mineralocorticoid genetics, Spironolactone therapeutic use
- Abstract
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.
- Published
- 2019
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