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Mineralocorticoid receptor pathway and its antagonism in a model of diabetic retinopathy

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posted on 23.08.2021, 11:09 by Min Zhao, Emmanuelle Gelize, Rinath Levy, Alexandre Moulin, Frédéric Azan, Marianne Berdugo, Marie-Christine Naud, Justine Guegan, Kimberley Delaunay, Eric Pussard, Patricia Lassiaz, Irene Bravo-Osuna, Rocio Herrero-Vanrell, Francine Behar-Cohen

Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and, that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetic complications regulated by MR are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage and retinal edema through the up-regulation of genes encoding proteins known to intervene in vascular permeability such as Hey1, Vldlr, Pten, Slc7a1, Tjp1, Dlg1 and Sesn2 but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.

Funding

The authors thank INSERM, the Agence Nationale de la Recherche (ANR Mineraloret ANR-11-BSV1-0022, and ROCK-SUR-MeR ANR-15-CE18-0032), the Swiss National Science Foundation (grant #156260 to C. R.), Fondation de l’Avenir and The Abraham J. & Phyllis Katz Foundation for financial support. This research was also supported by grants from MAT2017- 83858-C2- 1 MINECO/AEI/FEDER, Research Group UCM 920415, Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) and the ISCII-FEDER RETICS (OFTARED) (RD16/0008).

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