title: The aldosterone-mineralocorticoid receptor pathway exerts anti-inflammatory effects in endotoxin-induced uveitis.
abstract: We have previously shown that the eye is a mineralocorticoid-sensitive organ and we now question the role of mineralocorticoid receptor (MR) in ocular inflammation. The endotoxin-induced uveitis (EIU), a rat model of human intraocular inflammation, was induced by systemic administration of lipopolysaccharide (LPS). Evaluations were made 6 and 24 hours after intraocular injection of aldosterone (simultaneous to LPS injection). Three hours after onset of EIU, the MR and the glucocorticoid metabolizing enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression were down-regulated in iris/ciliary body and the corticosterone concentration was increased in aqueous humor, altering the normal MR/glucocorticoid receptor (GR) balance. At 24 hours, the GR expression was also decreased. In EIU, aldosterone reduced the intensity of clinical inflammation in a dose-dependent manner. The clinical benefit of aldosterone was abrogated in the presence of the MR antagonist (RU26752) and only partially with the GR antagonist (RU38486). Aldosterone reduced the release of inflammatory mediators (6 and 24 hours: TNF-α, IFN-γ, MIP-1α) in aqueous humor and the number of activated microglia/macrophages. Aldosterone partly prevented the uveitis-induced MR down-regulation. These results suggest that MR expression and activation in iris/ciliary body could protect the ocular structures against damages induced by EIU.
authors.affiliation: INSERM U872, Université René Descartes Sorbonne Paris Cité, Team 17, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bousquet
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: André
authors.initials: A
authors.lastname: Ly
authors.forename: Guillaume
authors.initials: G
authors.lastname: Leroux Les Jardins
authors.forename: Brigitte
authors.initials: B
authors.lastname: Goldenberg
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Naud
authors.forename: Laurent
authors.initials: L
authors.lastname: Jonet
authors.forename: Bernadette
authors.initials: B
authors.lastname: Besson-Lescure
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
authors.forename: Yvonne
authors.initials: Y
authors.lastname: De Kozak
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002924:Ciliary Body / Q000201:enzymology / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004731:Endotoxins; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D058449:Intravitreal Injections; D007498:Iris / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008070:Lipopolysaccharides; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000008:administration & dosage / Q000494:pharmacology; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D004731:Endotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2