Regulation of renal vitamin D receptor is an important determinant of 1alpha,25-dihydroxyvitamin D(3) levels in vivo.
The synthesis of 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is most strongly regulated by dietary calcium and the action of parathyroid hormone to increase 1alpha-hydroxylase (1alpha-OHase) and decrease 24-hydroxylase (24-OHase) in kidney proximal tubules. This study examines the hypothesis that 1,25-(OH)(2)D(3) 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 microg) remained hypocalcemic despite increasing levels of serum calcium in relation to the vitamin D dose. Plasma levels of 1,25-(OH)(2)D(3) 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)(2)D(3). In rats fed a 0.47% calcium diet (+Ca) supplemented with vitamin D (4 microg/day), exogenous 1,25-(OH)(2)D(3) suppressed renal 1alpha-OHase and stimulated the 24-OHase. In rats fed the -Ca diet, vitamin D was unable to suppress the renal 1alpha-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)(2)D(3) suppression of the 1alpha-OHase and upregulation of the 24-OHase in the kidney, causing a marked accumulation of 1,25-(OH)(2)D(3) in the plasma.
Beckman
Matthew J
MJ
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, 53706-1544, USA.
DeLuca
Hector F
HF
D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D002136:Calcium, Dietary / Q000008:administration & dosage; D003577:Cytochrome P-450 Enzyme System; D015536:Down-Regulation; D005246:Feedback; D006128:Growth / Q000502:physiology; D006996:Hypocalcemia / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D016105:Parathyroidectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013965:Thyroidectomy; D014018:Tissue Distribution; D015854:Up-Regulation; D065668:Vitamin D3 24-Hydroxylase
D002136:Calcium, Dietary; D018167:Receptors, Calcitriol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol