title: The neuroretina is a novel mineralocorticoid target: aldosterone up-regulates ion and water channels in Müller glial cells.
abstract: Glucocorticoids reduce diabetic macular edema, but the mechanisms underlying glucocorticoid effects are imperfectly elucidated. Glucocorticoids may bind to glucocorticoid (GR) and mineralocorticoid (MR) receptors. We hypothesize that MR activation may influence retinal hydration. The effect of the MR agonist aldosterone (24 h) on ion/water channel expression (real-time PCR, Western blot, immunofluorescence) was investigated on cultured retinal Müller glial cells (RMGs, which contribute to fluid homeostasis in the retina), in Lewis rat retinal explants, and in retinas from aldosterone-injected eyes. We evidenced cell-specific expression of MR, GR, and 11-beta-hydroxysteroid dehydrogenase type II. Aldosterone significantly enhances expression of sodium and potassium channels ENaC-alpha (6.5-fold) and Kir4.1 (1.9-fold) through MR and GR occupancy, whereas aquaporin 4 (AQP4, 2.9-fold) up-regulation is MR-selective. Aldosterone intravitreous injection induces retinal swelling (24% increase compared to sham-injected eyes) and activation of RMGs. It promotes additional localization of Kir4.1 and AQP4 toward apical microvilli of RMGs. Our results highlight the mineralocorticoid-sensitivity of the neuroretina and show that aldosterone controls hydration of the healthy retina through regulation of ion/water channels expression in RMGs. These results provide a rationale for future investigations of abnormal MR signaling in the pathological retina.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 872, Team 17, Centre de Recherche des Cordeliers, Université René Descartes, Paris, France.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Valamanesh
authors.forename: Isabelle
authors.initials: I
authors.lastname: Celerier
authors.forename: Michèle
authors.initials: M
authors.lastname: Savoldelli
authors.forename: Laurent
authors.initials: L
authors.lastname: Jonet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Jeanny
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000378:metabolism*; D000098854:Kcnj10 Channel
chemical_list: D051401:Aquaporin 4; D053503:Epithelial Sodium Channels; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003907:Dexamethasone