GLUCOMINERALORET · THE GLUCO- AND MINERALO-CORTICOID PATHWAYS IN RETINA: MOLECULAR CARACTERISATION AND THERAPEUTIC IMPLICATION

THE GLUCO- AND MINERALO-CORTICOID PATHWAYS IN RETINA: MOLECULAR CARACTERISATION AND THERAPEUTIC IMPLICATION

Macular edema is the main cause of vision loss due to diabetic retinopathy. Glucocorticoids (GC) are indicated to reduce macular edema of various origins comprising diabetic macular edema DME) . While efficient, GC induces frequent and severe side-effects (cataract and glaucoma) and their exact mechanisms of action remain imperfectly understood. It is crucial to fill the gaps in the fundamental knowledge of the gluco- and associated mineralo-corticoid systems as well as in DME physiopathology. In this regard, the project objectives were: i) -to elucidate the specific implications of the gluco- and mineralo-corticoid receptors (GR/MR) in the normal retina, ii) -to better understand the diabetic-induced retinal deregulation and its contribution to edema formation, iii) –and to identify new players/targets for the treatment of DME. For that purpose, proteomic and genomic large-scale and up-to-date techniques (mass spectrometry and RNA-sequencing) were used on rat retina to identify the GR/MR protein cofactors, the dynamics of their interactions, as well as the genes and cellular functions regulated by the in vivo administration of their ligands (corticosterone and aldosterone). In addition, the genes and functions deregulated in the retina of a diabetic rat model have been studied in parallel by RNA-sequencing at both an early and late stages of the disease (type2 diabetes). Moreover, because DME is specific to a restricted portion of the retina found only in human and primates -the macula- we also used a monkey retina to highlight the gene expression pattern that makes this region so specific (as compared to peripheral retinal regions), and focus our interest on genes which would have higher relevance in human. Thus, our large-scale project allowed to significantly progress in the basic knowledge of the genomic and non-genomic mechanisms of action of the gluco- and mineralo-corticoid systems in vivo in the retina, both in physiological condition and after stimulation by their natural ligand (corticosterone and aldosterone). Glucocorticoids seem to exert a wide panel of actions with emerging novel (and strongly represented) functions and molecular players often specific to retina and depending on the ligand-receptor interaction. Crossed data analyses, biocomputing and bibliographical study of the identified protein and gene players allowed us to establish a restricted list of new potential therapeutic targets for anti-edematous treatments. The non-genomic molecular players of the corticoid pathways, in particular those involved in aqueous and ionic flows, could explain the rapid anti-edematous effects observed in DME patient treated by glucocorticoids and are the main focus of on-going studies. Our work also highlighted the genes that could be involved in the ocular side effects of corticoids (glaucoma and cataract), with a final aim to potentiate the therapeutic effect of glucocorticoids for a real restoration of vision in DME patients. In summary, our large-scale project identifies i) the mechanisms of action of corticosterone, aldosterone and their receptors in vivo in the rat neuroretina, ii) the deregulated mechanisms of diabetic retinopathy, iii) the molecular characteristics of the retinal zone susceptible to edema formation. Glucocorticoids seem to exert a wide panel of actions with emerging (and strongly represented) novel functions, and molecular players often specific to retina and depending on the ligand-receptor interaction. The crossed analysis of our studies allowed obtaining a restricted list of the new potential therapeutic targets for the treatment of edematous retinal pathologies. The non-genomic molecular players of the corticoid pathways involved in aqueous and ionic flows could explain the rapid effects observed in patient with DME and treated with glucocorticoids and are the main focus of on-going and future studies. Our work also highlights genes potentially involved in ocular side effects of corticoids (glaucoma and cataract)

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