Adrenal and Glucocorticoid Effects on the Circadian Rhythm of Murine Intraocular Pressure

PURPOSE: Intraocular pressure (IOP) fluctuates with a robust circadian rhythm, which is synchronized to organismal rhythmicity through the master circadian clock located in the suprachiasmatic nuclei. The mechanisms maintaining circadian synchrony between the suprachiasmatic nuclei and IOP rhythms are presently unknown. The purpose of this study was to evaluate the necessity and sufficiency of adrenal and glucocorticoid function for the entrainment of iris-ciliary body (iris-CB) and IOP circadian rhythms in mice. METHODS: Iris-CB complexes were dissected from C57Bl/6J mice that were kept in 12-hour light/dark cycles at 3-hour intervals, and their core clock gene (Per1, Per2, and Bmal1) and glucocorticoid receptor mRNA expression were quantified. Iris-CB complexes from period2::luciferase mice were dissected and cultured to measure in vitro rhythmicity. To determine the phase-shifting effect of glucocorticoids on the iris-CB, dexamethasone or vehicle was added to the cultured tissues at defined circadian phases. The diurnal IOP rhythms of adrenalectomized or sham-operated mice under the 12-hour light/dark cycles were also measured. RESULTS: In iris-CB complexes, glucocorticoid receptor mRNA expression remained stable throughout the day, whereas the mRNA of core clock genes showed a robust circadian rhythmicity. Dexamethasone significantly induced phase-delays when administered between circadian time 8 (CT8) to CT12 and phase-advance when given between CT16 to CT20. Adrenalectomy abolished circadian IOP rhythmicity, particularly diminishing nocturnal IOP elevation compared with sham-operated mice. CONCLUSIONS: Glucocorticoids are sufficient for phase shifting the circadian clock in iris-CB. Intact adrenal function is required for manifest circadian rhythms of IOP in mice. Taken together, these data are consistent with the hypothesis that glucocorticoids mediate circadian entrainment of IOP to the master circadian oscillator.