Effects of vitamin D compounds on renal and intestinal Ca2+ transport proteins in 25-hydroxyvitamin D3-1α-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 Ca2+-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 Ca2+ transport proteins, including TRPV5 and TRPV6, and serum Ca2+, 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 Ca2+ 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. Conclusion. In kidney, 1alpha(OH)D-2 increased TRPV5, calbindin-D-28K, and calbindin-D-9K mRNA levels by 12 hours. This study indicates that Ca2+ transport proteins, including TRPV5 and TRPV6, are differentially up-regulated by vitamin D compounds.