Comparative in vivo expression of the calcitriol-24-hydroxylase gene in kidney and intestine

Although the kidney and intestine are among the major organs involved in both the biotransformation and action of vitamin D-3, they exhibit very distinct roles in calcium and D-3 homeostasis. The aim of the present studies was to investigate the relative in vivo responsiveness of renal and intestinal 1,25(OH)(2)D-3-24-hydroxylase (24-hydroxylase) mRNA levels to calcitriol (1,25(OH)(2)D-3) following acute or chronic 1,25(OH)(2)D-3 exposure using hypocalcemic vitamin D-depleted rats as an experimental model. Intestinal 24-hydroxylase mRNA levels were very responsive to a single i.v. injection of 2.4, 12 or 120 nmol 1,25(OH)(2)D-3/kg but in kidney the mRNA levels only increased following exposure to the highest 1,25(OH)(2)D-3 concentration, and exhibited a maximum response only 30% of that in the intestine despite similar tissue uptake of the hormone. To evaluate whether the kidney might preferentially respond to endogenously produced 1,25(OH)(2)D-3, animals received increasing doses of 25(OH)D-3. Although the intestinal 24-hydroxylase transcript was highly induced, the renal transcript was unresponsive to 25(OH)D-3 treatment despite circulating 1,25(OH)(2)D-3 concentrations of 24 nmol/l. By contrast, intestinal 24-hydroxylase mRNA levels were largely unresponsive to longterm calcitriol administration while the renal transcript, although insensitive to a physiological dose, responded to pharmacological 1,25(OH)(2)D-3 doses. However, when challenged acutely with following chronic exposure, the kidney 24-hydroxylase mRNA levels largely unresponsive in contrast to the transcript which was markedly induced. These data indicate that significant differences exist in the in vivo tissue responsiveness of the 24-hydroxylase mRNA. Indeed, the gene exhibited high intestinal responsiveness to acutely, but not chronically, administered 1,25(OH)(2)D-3, while in the kidney it only responded to high exogenous 1,25(OH)(2)D-3 delivered either acutely or chronically. In addition, these site-specific regulatory mechanisms governing the expression of the 24-hydroxylase gene are independent of the endocrine calcium status and render the kidney relatively resistant to endogenously produced 1,25(OH)(2)D-3.