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J.L. Ubels, E.D. Veenstra, J.A. Ditlev, K.E. Ingersoll; Retinoic Acid Inhibits Androgen-Stimulated Up-Regulation of Androgen Receptor Expression in Lacrimal Glands of Orchiectomized Rats . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1023.
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Purpose: It is thought that androgens are required for normal lacrimal gland function. Androgen receptor (AR) protein expression is decreased in lacrimal glands of orchiectomized rats and treatment with testosterone restores AR expression (Rocha et al., J Steroid Biochem Mol Biol. 46:737, 1993). Treatment of rabbit lacrimal gland acinar cells in culture with all-trans retinoic acid (RA) down-regulates expression of AR mRNA and protein (Ubels et al. Exp Eye Res. 75:561, 2002). The goal of this study was to determine if retinoic acid inhibits androgen-stimulated up-regulation of androgen receptor protein expression in lacrimal glands of orchiectomized rats. Methods: Rat lacrimal gland acinar cells in culture were treated with 10-6M RA and total RNA was probed for AR mRNA expression. Orchiectomized rats were injected with a single dose of Depotestosterone at 2.5-25 mg/kg and treated with RA at 20 or 50 mg/kg/day by gastric gavage. After 7 days lacrimal glands were removed, AR protein expression in frozen sections was determined by immunohistochemistry and image analysis, total RNA was probed for AR mRNA expression and serum testosterone was measured by ELISA. Results: As in rabbits, RA down-regulates AR mRNA in rat lacrimal acinar cells in culture. Orchiectomy decreases serum testosterone to 17 ng/dl, compared to143 ng/dl in normal rats, and reduces the number of lacrimal acinar cell nuclei expressing AR to <30% of normal. Serum testosterone ranged from 62 ng/dl after a 2.5 mg/kg dose of Depotestosterone to 319 ng/dl after a 25 mg/kg dose. Over this range of testosterone doses, AR expression in lacrimal gland nuclei was restored to 60-100% of normal. Treatment of orchiectomized rats with RA (20 or 50 mg/kg/d) simultaneously with testosterone (2.5 mg/kg) prevented restoration of lacrimal gland AR expression and significantly reduced AR mRNA expression. Conclusions: A pharmacologic dose of retinoic acid inhibits AR expression in lacrimal gland acinar cells in vivo, as well as in vitro. This agrees with data from other organs, such as prostate and sebaceous glands, and indicates that effects of retinoic acid and testosterone are generally antagonistic. The implications of this observation for lacrimal gland function in health or disease are unknown, especially since AR expression is not completely inhibited; however, it is suggested that retinoic acid may modulate effects of testosterone in the lacrimal gland.
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