The glucocorticoid receptor is essential for maintaining basal and dexamethasone-induced repression of the murine corticosteroid-binding globulin gene.
We have investigated hepatic expression and glucocorticoid regulation of the corticosteroid-binding globulin (CBG) gene in mice lacking a functional glucocorticoid receptor (GR). GR-/- mice show impaired negative feedback in the hypothalamic-pituitary-adrenal axis, resulting in elevated circulating levels of ACTH and corticosterone. This is seen in the neonatal period and continues into adulthood where ACTH and corticosterone levels are increased up to 4-5 fold. Despite high elevation of corticosterone we find no change in mean arterial blood pressure in GR-/- mice and no change in the renal activity of the glucocorticoid-metabolising enzymes 11beta-hydroxysteroid dehydrogenase type-1 (HSD1) and type-2 (HSD2). We do find markedly increased hepatic expression of CBG with a 50% increase in plasma CBG levels. Increased expression of CBG was detected in adult GR-/- mice and also at birth with a greater than 10-fold increase in CBG hepatic mRNA in day-18.5 embryonic GR-/- mice. Adult GR-/- mice were also resistant to dexamethasone-induced repression of CBG expression in the liver. These results indicate that in mice, GR is essential for maintaining the basal level of CBG gene expression in the liver, and is also required for dexamethasone-induced repression of the CBG gene in the adult.
Cole
T J
TJ
Baker Medical Research Institute, Prahran, Victoria, Australia. tim.cole@baker.edu.au
Harris
H J
HJ
Hoong
I
I
Solomon
N
N
Smith
R
R
Krozowski
Z
Z
Fullerton
M J
MJ
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014156:Transcortin / Q000187:drug effects / Q000235:genetics*
D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D014156:Transcortin; D003345:Corticosterone