Regulation of renal vitamin D hydroxylase activity in vitamin D deficient rats

Abstract

The regulation of renal mitochondrial 1-hydroxylase activity in chronic vitamin D deficiency was studied in male rats. These rats were born of mothers who had been raised from weaning (21 days) on a vitamin D deficient diet and who had no detectable serum 1,25-dihydroxycholecalciferol (1,25-(OH)2D) at the time their offspring were weaned (28 days). In the pups, renal mitochondrial 1-hydroxylase activity was undetectable before the 3rd week of life even though the animals were severely hypocalcemic from birth. The 1-hydroxylase activity first became detectable at 26 days of age, rapidly reached a maximum at day 34, then decreased to become undetectable again by 65 days. Throughout this time serum calcium concentration was <5.0 mg/dL and serum parathyroid hormone (PTH) concentration, measured by a midmolecule radioimmunoassay, was two-to five-fold greater than that found in vitamin D replete rats. 1-Hydroxylase activity could be restored in the +65-day-old animals by administration of a single dose of 2.5 μg vitamin D3. Enzyme activity was detected within 24 h, was maximal at 72 h, and returned to undetectable levels by 96 h after administration of the vitamin. Serum 1,25-(OH)2D which was undetectable before administration of the vitamin D3, was 108 and 458 pg/mL at 16 and 40 h, respectively, after the injection. The serum concentration of this metabolite then decreased progressively to 80 pg/mL by 6 days. 24-Hydroxylase activity first became detectable 48 h after vitamin D administration, increased to a maximum at 96 h, and thereafter decreased to become undetectable by 7 days. The urinary excretion of phosphate and cyclic AMP was 10% of control values between 65 and 90 days of age. These values became normal 4 days after a single dose of 2.5 μg vitamin D3. From these data it is concluded that there are two distinct levels of regulation of 1-hydroxylase activity: a vitamin D independent induction of the activity at the time of weaning that is transient and is not associated with any detectable 24-hydroxylase activity; and the second is a vitamin D dependent induction of enzyme activity seen in animals which prior to administration of the vitamin manifest the characteristics of PTH resistance and have no detectable renal hydroxylase activity. The mechanisms of these effects remain to be determined.