Effects of vitamin D compounds on renal and intestinal Ca2+ transport proteins in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice.
BACKGROUND
Vitamin D compounds are used clinically to control secondary hyperparathyroidism (SHPT) due to renal failure. Newer vitamin D compounds retain the suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands and may have less Ca(2+)-mobilizing activity, offering potentially safer therapies.


METHODS
This study investigated the effect of a single dose of compound (1,25(OH)(2)D(3), 1,24(OH)(2)D(2), or 1alpha(OH)D(2)) on renal and intestinal Ca(2+) transport proteins, including TRPV5 and TRPV6, and serum Ca(2+), in a novel SHPT model, the 25-OH-D(3)-1alpha-hydroxylase knockout mouse, which lacks endogenous 1,25(OH)(2)D(3) and is severely hypocalcemic. Animals were injected intraperitoneally with compound (100 ng/mouse).


RESULTS
Serum levels of 1,25(OH)(2)D(3) and 1,24(OH)(2)D(2) peaked at four hours post-injection (pi), then declined rapidly. 1,25(OH)(2)D(2) generated from 1alpha(OH)D(2) peaked at 12 hours pi and then remained stable. Serum Ca(2+) was increased to near-normal within four hours by 1,25(OH)(2)D(3) and 1,24(OH)(2)D(2), and within 12 hours by 1alpha(OH)D(2). 1,25(OH)(2)D(3) and 1,24(OH)(2)D(2) up-regulated duodenal TRPV5 and TRPV6 mRNA to a similar degree within four hours; mRNA levels decreased by 12 hours after 1,24(OH)(2)D(2) treatment, and by 24 hours after 1,25(OH)(2)D(3) treatment. 1,25(OH)(2)D(3) increased kidney levels of TRPV5, calbindin-D(28K), and calbindin-D(9K) mRNA within four hours; 1,24(OH)(2)D(2) did not change kidney TRPV5 levels and modestly increased calbindin D(9K) by 48 hours. 1alpha(OH)D(2) produced later-onset effects, increasing duodenal TRPV6 and calbindin-D(9K) mRNA levels by 12 hours and TRPV5 by 48 hours.


CONCLUSIONS
In kidney, 1alpha(OH)D(2) increased TRPV5, calbindin-D(28K), and calbindin-D(9K) mRNA levels by 12 hours. This study indicates that Ca(2+) transport proteins, including TRPV5 and TRPV6, are differentially up-regulated by vitamin D compounds.
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre Nijmegen, The Netherlands.
Joost G J
JG
Hoenderop
Annemiete W C M
AW
van der Kemp
Colleen M
CM
Urben
Stephen A
SA
Strugnell
René J M
RJ
Bindels
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D064026:Calbindins; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000378:metabolism
D064026:Calbindins; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D004872:Ergocalciferols; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; D050916:TRPV Cation Channels; C120776:TRPV6 channel; C492240:Trpv5 protein, mouse; C063087:1,24-dihydroxyvitamin D2; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium