Regulation of vitamin D-1alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney.
We investigated the effects of dexamethasone on vitamin D-1alpha-hydroxylase and -24-hydroxylase expression and on vitamin D receptor (VDR) content in the kidneys of mice fed either a normal (NCD) diet or a calcium- and vitamin D-deficient (LCD) diet for 2 weeks. For the last 5 days mice received either vehicle or dexamethasone (2 mg/kg per day s.c.). Dexamethasone significantly increased plasma calcium concentrations without changing plasma concentrations of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) in both NCD and LCD groups. Northern blot and enzyme activity analyses in NCD mice revealed that dexamethasone increased renal VDR mRNA expression modestly and greatly increased 24-hydroxylase mRNA abundance and enzyme activity, but did not affect 1alpha-hydroxylase mRNA abundance and enzyme activity. In mice fed an LCD diet, dexamethasone increased renal VDR mRNA expression 1.5-fold, decreased 1alpha-hydroxylase mRNA abundance (52%) and activity (34%), and markedly increased 24-hydroxylase mRNA abundance (16-fold) and enzyme activity (9-fold). Dexamethasone treatment did not alter functional VDR number (B(max) 125-141 fmol/mg protein) or ligand affinity (K(d) 0.13-0.10 nM) in LCD mice. Subcutaneous injections of 1,25(OH)(2)D(3) (0.24 nmol/kg per day for 5 days) into NCD mice strongly increased renal 24-hydroxylase mRNA abundance and enzyme activity, while there was no effect of dexamethasone on renal 24-hydroxylase expression in these mice. This may be due to overwhelming induction of 24-hydroxylase by 1,25(OH)(2)D(3). These findings suggest that glucocorticoid-induced osteoporosis is caused by direct action of the steroids on bone, and the regulatory effect of glucocorticoids on renal 25-hydroxyvitamin D(3) metabolism may be less implicated in the initiation and progression of the disease.
Akeno
N
N
Department of Biochemistry, Ohu University School of Dentistry, Koriyama 963-8611, Japan.
Matsunuma
A
A
Maeda
T
T
Kawane
T
T
Horiuchi
N
N
D000818:Animals; D015152:Blotting, Northern; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000008:administration & dosage / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D010758:Phosphorus / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014807:Vitamin D / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000201:enzymology*; D065668:Vitamin D3 24-Hydroxylase
D005938:Glucocorticoids; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014807:Vitamin D; D010758:Phosphorus; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium