Responsiveness of the intestinal 1,25-dihydroxyvitamin D3 receptor to magnesium depletion in the rat

Abstract

In contrast to man, the rat exhibits hypercalcemia during the course of magnesium depletion. To investigate the role of the vitamin D (D) endocrine system in the induction of hypercalcemia, circulating D metabolites, the binding properties of the duodenal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), and 45Ca transport studies were undertaken in magnesium-replete rats or after 10 days of magnesium depletion in animals presenting the following D status: D depletion and hypo- or normocalcemia (achieved by oral calcium supplementation), D3 or 1,25-(OH)2D3 repletion. Magnesium depletion did not influence serum calcium in hypo- or normocalcemic D depleted rats, but increased serum calcium in animals receiving D3 (P less than 0.002) or 1,25-(OH)2D3 (P less than 0.0001), suggesting that the D3 endocrine system is necessary to mediate the rise in extracellular calcium and that dietary calcium alone is not sufficient to significantly increase extracellular calcium in the hypomagnesemic rat. The data also show that 25-hydroxyvitamin D formation was not perturbed, but circulating 1,25-(OH)2D3 concentrations were reduced by 10 days of magnesium depletion (P less than 0.0001) even in animals infused with 1,25-(OH)2D3, suggesting increased clearance of the hormone. The kinetic data of the duodenal VDR revealed maximum binding sites ranging from 1018-1500 fmol/mg DNA and Kd ranging from 0.17-0.38 nM, with no significant between-group difference in magnesium-sufficient animals. Ten days of magnesium depletion did not significantly influence VDR affinity in any of the groups, but significantly increased receptor number in hypocalcemic D-depleted rats from 1190 +/- 154 to 2748 +/- 430 fmol/mg DNA (P less than 0.004). Calcium transport studies in D-replete animals indicate that intestinal calcium transport is influenced by the progressive depletion in magnesium, with time-related increases coinciding with the in vivo increase in circulating ionized calcium (day 6 of magnesium depletion). However, despite persistent elevated serum ionized calcium, calcium transport declined only to predepletion levels on days 8 and 10 of magnesium depletion. To investigate the influence of the D3 endocrine system on 45Ca absorption, D-depleted rats sufficient or depleted in magnesium were injected with 1,25-(OH)2D3, either acutely (to reveal its membrane effects) or 16 and 5 h before death (to reveal its genomic effect). The data reveal a reduced response in magnesium-depleted rats to acute 1,25-(OH)2D3 injection (P less than 0.0002), but similar responses when the hormone was injected 16 and 5 h before the experiment.(ABSTRACT TRUNCATED AT 400 WORDS)