Regulation of renal vitamin D receptor is an important determinant of 1α,25-dihydroxyvitamin D3 levels in vivo

The synthesis of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is most strongly regulated by dietary calcium and the action of parathyroid hormone to increase 1α-hydroxylase (1α-OHase) and decrease 24-hydroxylase (24-OHase) in kidney proximal tubules. This study examines the hypothesis that 1,25-(OH)2D3 synthesis, induced by dietary calcium restriction, is also the result of negative feedback regulation blockade. Rats fed a low calcium (0.02%, −Ca) diet and given daily oral doses of vitamin D (0, 0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 μg) remained hypocalcemic despite increasing levels of serum calcium in relation to the vitamin D dose. Plasma levels of 1,25-(OH)2D3 rose to high levels (1200 pg/ml) at the high vitamin D dose levels. As expected, thyroparathyroidectomy caused a rapid fall in serum 1,25-(OH)2D3. In rats fed a 0.47% calcium diet (+Ca) supplemented with vitamin D (4 μg/day), exogenous 1,25-(OH)2D3 suppressed renal 1α-OHase and stimulated the 24-OHase. In rats fed the −Ca diet, vitamin D was unable to suppress the renal 1α-OHase or stimulate the renal 24-OHase. In contrast, vitamin D was fully able to stimulate intestinal 24-OHase. Intestinal vitamin D receptor (VDR) was present under all circumstances, while kidney VDR was absent under hypocalcemic conditions and present under normocalcemic conditions. It appears that tissue-specific down-regulation of VDR by hypocalcemia blocks the 1,25-(OH)2D3 suppression of the 1α-OHase and upregulation of the 24-OHase in the kidney, causing a marked accumulation of 1,25-(OH)2D3 in the plasma.