11Beta-Hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) catalyse the synthesis of corticosterone and aldosterone respectively in the rat adrenal cortex. Recent studies have shown that CYP11B1 and CYP11B2 are also expressed in the central nervous system (CNS) but little is known about their regulation. In this study, we have quantified CYP11B1 and CYP11B2 gene expression in the CNS following treatment with ACTH and dexamethasone.
Three groups of male Wistar rats (n=6) were given vehicle, ACTH (40nanograms/day) or dexamethasone (10micrograms/day) by osmotic mini-pumps for 7 days. RNA was isolated and gene expression was quantified using real-time RT-PCR.
ACTH treatment increased adrenal weight 3-fold (p<0.01), fecal corticosterone 100-fold (P<0.01) and fecal aldosterone 10-fold (P<0.01). Plasma renin activity was suppressed. Allowing for changes in tissue mass, ACTH increased CYP11B1 expression in adrenal glands (3.3-fold, P<0.05), hypothalamus (1.7-fold, P<0.05) and cerebral cortex (2.0-fold, P<0.05). CYP11B2 expression was decreased by ACTH in the adrenal gland (40-fold, P<0.01) but was increased in the hippocampus (2.0-fold, P<0.05) and hypothalamus (2.6-fold, P<0.05). Dexamethasone halved CYP11B1 expression in the adrenal gland (P<0.05) but had no significant effect on the CNS.
ACTH-mediated hypertrophy of the adrenal gland probably accounts for the increase in total adrenal CYP11B1 mRNA expression and the dramatic increase in corticosterone secretion. ACTH-induced expression of CYP11B1 in the hypothalamus and cerebral cortex occurs independently of tissue mass and, since ACTH does not cross the blood brain barrier, may be mediated by ACTH fragments or by high circulating levels of corticosterone. Inhibition of CYP11B2 expression with ACTH is associated with suppression of the renin-angiotensin system and may reflect the mineralocorticoid properties of the increased corticosterone. Extra-adrenal sites of synthesis may account for the presence of fecal aldosterone despite decreased adrenal CYP11B2 expression.
22 - 24 Mar 2004
British Endocrine Societies