Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration.
journal contributionposted on 20.08.2019, 11:45 by M Zhao, I Mantel, E Gelize, X Li, X Xie, A Arboleda, M Seminel, R Levy-Boukris, M Dernigoghossian, A Prunotto, C Andrieu-Soler, C Rivolta, J Canonica, M-C Naud, S Lechner, N Farman, I Bravo-Osuna, R Herrero-Vanrell, F Jaisser, F Behar-Cohen
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.
We thank INSERM, the Agence Nationale de la Recherche (ANR Mineraloret ANR-11-BSV1–0022, and ROCK-SUR-MeR ANR-15-CE18–0032), the Fondation pour la Recherche Médicale (FRM Visual System 2013, DVS20131228894) and the Swiss National Science Foundation (grant #156260 to C. R.) for financial support. This research was also supported by grants from MAT2013–43127- R and MAT2017–83858-C2–1 MINECO/AEI/FEDER, UE. We thank Christophe Klein from Center d’Histologie, d’Imagerieet de Cytométrie, and Georges Zadigue from Center d’Explorations Fonctionnelles of Center de Recherche des Cordeliers for their technical support. We thank Maëva Dupuis-Deniaud, MDSTAT Consulting Lyon, France for her assistance in the statistical analysis.
CitationNature Communications, 2019, volume 10, Article number: 369
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology
VersionVoR (Version of Record)
Published inNature Communications
PublisherNature Research (part of Springer Nature)
NotesAll relevant data are available from the corresponding author upon reasonable request. RNA-sequencing data are available from ArrayExpress database at EMBL-EBI under accession number E-MTAB-7438. The images from figures are available at figshare https://figshare.com/articles/Antagonism_of_the_mineralocorticoid_pathway_limits_choroidal_neovascularization/7283648 . A Reporting Summary for this Article is available as a Supplementary Information file.
AgedAged, 80 and overAngiogenesis InhibitorsAnimalsChoroidChoroidal NeovascularizationDrug CompoundingFemaleGene ExpressionHumansIntravitreal InjectionsMacular DegenerationMaleMiceMice, TransgenicMicrospheresMineralocorticoid Receptor AntagonistsPilot ProjectsProspective StudiesRanibizumabRats, Long-EvansReceptors, MineralocorticoidReceptors, Vascular Endothelial Growth FactorRecombinant Fusion ProteinsSpironolactoneTreatment OutcomeVascular Endothelial Growth Factor A