Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration

Min Zhao; Irmela Mantel; Emmanuelle Gelize; Xinxin Li; Xiaoyue Xie; Alejandro Arboleda; Marie Seminel; Rinath Levy-Boukris; Marilyn Dernigoghossian; Andrea Prunotto; Charlotte Andrieu-Soler; Carlo Rivolta; Jérémie Canonica; Marie-Christine Naud; Sebastian Lechner; Nicolette Farman; Irene Bravo-Osuna; Rocio Herrero-Vanrell; Frederic Jaisser; Francine Behar-Cohen

doi:10.1038/s41467-018-08125-6

Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration

Nat Commun. 2019 Jan 21;10(1):369. doi: 10.1038/s41467-018-08125-6.

Authors

Min Zhao^{1

2

3}, Irmela Mantel⁴, Emmanuelle Gelize^{1

2

3}, Xinxin Li^{1

2

3}, Xiaoyue Xie^{1

2

3}, Alejandro Arboleda^{1

2

3

5}, Marie Seminel^{1

2

3}, Rinath Levy-Boukris^{1

2

3}, Marilyn Dernigoghossian^{1

2

3}, Andrea Prunotto⁶, Charlotte Andrieu-Soler⁷, Carlo Rivolta^{6

8}, Jérémie Canonica⁴, Marie-Christine Naud^{1

2

3}, Sebastian Lechner^{2

3

9}, Nicolette Farman^{2

3

9}, Irene Bravo-Osuna^{10

11

12}, Rocio Herrero-Vanrell^{10

11

12}, Frederic Jaisser^{2

3

9}, Francine Behar-Cohen^{13

14

15

16}

Affiliations

¹ Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, 75006, Paris, France.
² Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, 75006, Paris, France.
³ Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006, Paris, France.
⁴ Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, 1004, Lausanne, Switzerland.
⁵ Ophthalmic Biophysics Center, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
⁶ Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011, Lausanne, Switzerland.
⁷ IGMM, CNRS, Univ. Montpellier, 34293, Montpellier Cedex 5, France.
⁸ Department of Genetics and Genome Biology, University of Leicester, Leicester, LE1 7RH, UK.
⁹ Inserm UMR_S 1138, Team 1, Centre de Recherche des Cordeliers, 75006, Paris, France.
¹⁰ Department of Pharmacy and Pharmaceutical Technology, Universidad Complutense de Madrid, 28040, Madrid, Spain.
¹¹ Instituto Universitario de Farmacia Industrial, Faculty of Pharmacy, Universidad Complutense de Madrid, 28040, Madrid, Spain.
¹² Fundación para la Investigación-HCSC, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040, Madrid, Spain.
¹³ Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, 75006, Paris, France. [email protected].
¹⁴ Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, 75006, Paris, France. [email protected].
¹⁵ Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006, Paris, France. [email protected].
¹⁶ Assistance Publique - Hôpitaux de Paris, Hôtel-Dieu de Paris, 75004, Paris, France. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Angiogenesis Inhibitors / therapeutic use*
Animals
Choroid / drug effects
Choroid / metabolism
Choroid / pathology
Choroidal Neovascularization / drug therapy*
Choroidal Neovascularization / genetics
Choroidal Neovascularization / metabolism
Choroidal Neovascularization / pathology
Drug Compounding / methods
Female
Gene Expression
Humans
Intravitreal Injections
Macular Degeneration / drug therapy*
Macular Degeneration / genetics
Macular Degeneration / metabolism
Macular Degeneration / pathology
Male
Mice
Mice, Transgenic
Microspheres
Mineralocorticoid Receptor Antagonists / therapeutic use*
Pilot Projects
Prospective Studies
Ranibizumab / therapeutic use
Rats, Long-Evans
Receptors, Mineralocorticoid / genetics*
Receptors, Mineralocorticoid / metabolism
Receptors, Vascular Endothelial Growth Factor / therapeutic use
Recombinant Fusion Proteins / therapeutic use
Spironolactone / therapeutic use*
Treatment Outcome
Vascular Endothelial Growth Factor A / antagonists & inhibitors
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism

Substances

Angiogenesis Inhibitors
Mineralocorticoid Receptor Antagonists
Receptors, Mineralocorticoid
Recombinant Fusion Proteins
VEGFA protein, human
Vascular Endothelial Growth Factor A
aflibercept
Spironolactone
Receptors, Vascular Endothelial Growth Factor
Ranibizumab

Grants and funding

F05 AT002013/AT/NCCIH NIH HHS/United States