Regulation of vitamin D-1 alpha-hydroxylase and-24-hydroxylase expression by dexamethasone in mouse kidney

We investigated the effects of dexamethasone on vitamin D-1 alpha-hydroxyla se and -24-hydroxylase expression and on vitamin D receptor (VDR) content i n the kidneys of mice fed either a normal (NCD) diet or a calcium- and vita min D-deficient (LCD) diet for 2 weeks. For the last 5 days mice received e ither vehicle or dexamethasone (2 mg/kg per day s.c.). Dexamethasone signif icantly increased plasma calcium concentrations without changing plasma con centrations of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) in both NCD and L CD 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 a ffect 1 alpha-hydroxylase mRNA abundance and enzyme activity. In mice fed a n LCD diet, dexamethasone increased renal VDR mRNA expression 1.5-fold, dec reased 1 alpha-hydroxylase mRNA abundance (52%) and activity (34%), and mar kedly increased -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 day s) into NCD mice strongly increased renal 24-hydroxylase mRNA abundance and enzyme activity, while there was no effect of dexamethasone on renal 24-hy droxylase expression in these mice. This may be due to overwhelming inducti on of 24-hydroxylase by 1,25(OH)(2)D-3. These findings suggest that glucoco rticoid-induced osteoporosis is caused by direct action of the steroids on bone, and the regulatory effect of glucocorticoids on renal 25-hydroxyvitam in D-3 metabolism may be less implicated in the initiation and progression of the disease.