Effects of vitamin D compounds on renal and intestinal Ca2+ transport proteins in 25-hydroxyvitamin D3-1α-hydroxylase knockout mice1

Effects of vitamin D compounds on renal and intestinal Ca 2+ transport proteins in 25-hydroxyvitamin D 3 -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 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 1α(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 -1α-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 1α(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 1α(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. 1α(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, 1α(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.