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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics
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11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
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Aldosterone / administration & dosage
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Aldosterone / pharmacology
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Animals
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Anti-Inflammatory Agents / metabolism*
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use
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Aqueous Humor / drug effects
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Aqueous Humor / metabolism
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Chemokines / metabolism
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Ciliary Body / enzymology
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Ciliary Body / pathology
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Endotoxins
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Female
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Humans
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Inflammation Mediators / metabolism
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Intravitreal Injections
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Iris / drug effects
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Iris / enzymology
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Iris / pathology
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Lipopolysaccharides
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Microglia / drug effects
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Microglia / metabolism
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Microglia / pathology
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Rats
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Rats, Inbred Lew
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism
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Receptors, Mineralocorticoid / genetics
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Receptors, Mineralocorticoid / metabolism*
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Signal Transduction* / drug effects
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Spironolactone / administration & dosage
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Spironolactone / pharmacology
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Uveitis / chemically induced
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Uveitis / drug therapy
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Uveitis / metabolism*
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Uveitis / pathology*
Substances
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Anti-Inflammatory Agents
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Chemokines
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Endotoxins
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Inflammation Mediators
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Lipopolysaccharides
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Receptors, Glucocorticoid
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Receptors, Mineralocorticoid
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Spironolactone
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Aldosterone
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11-beta-Hydroxysteroid Dehydrogenase Type 2
Grants and funding
The Fondation pour la Recherche Medicale is acknowledged for supporting Elodie Bousquet. This work has been supported by INSERM funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.