Ion Channels – Membrane Transport – Integrative Physiology

Kidney International (2004) 66, 1082–1089; doi:10.1111/j.1523-1755.2004.00858.x

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

JOOST G J HOENDEROP, ANNEMIETE W C M VAN DER KEMP, COLLEEN M URBEN, STEPHEN A STRUGNELL and RENÉ J M BINDELS

Department of Physiology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre Nijmegen, The Netherlands; and Bone Care International, Middleton, Wisconsin

Correspondence: René J.M. Bindels, 160 Physiology University Medical Centre Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands. E-mail:r.bindels@ncmls.kun.nl

1See Editorial by Goodman, p. 1286.

Received 16 January 2004; Revised 24 March 2004; Accepted 16 April 2004.

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Abstract

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)2D3 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)2D3, 1,24(OH)2D2, or 1alpha(OH)D2) on renal and intestinal Ca2+ transport proteins, including TRPV5 and TRPV6, and serum Ca2+, in a novel SHPT model, the 25-OH-D3-1alpha-hydroxylase knockout mouse, which lacks endogenous 1,25(OH)2D3 and is severely hypocalcemic. Animals were injected intraperitoneally with compound (100 ng/mouse).

Results

 

Serum levels of 1,25(OH)2D3 and 1,24(OH)2D2 peaked at four hours post-injection (pi), then declined rapidly. 1,25(OH)2D2 generated from 1alpha(OH)D2 peaked at 12 hours pi and then remained stable. Serum Ca2+ was increased to near-normal within four hours by 1,25(OH)2D3 and 1,24(OH)2D2, and within 12 hours by 1alpha(OH)D2. 1,25(OH)2D3 and 1,24(OH)2D2 up-regulated duodenal TRPV5 and TRPV6 mRNA to a similar degree within four hours; mRNA levels decreased by 12 hours after 1,24(OH)2D2 treatment, and by 24 hours after 1,25(OH)2D3 treatment. 1,25(OH)2D3 increased kidney levels of TRPV5, calbindin-D28K, and calbindin-D9K mRNA within four hours; 1,24(OH)2D2 did not change kidney TRPV5 levels and modestly increased calbindin D9K by 48 hours. 1alpha(OH)D2 produced later-onset effects, increasing duodenal TRPV6 and calbindin-D9K mRNA levels by 12 hours and TRPV5 by 48 hours.

Conclusion

 

In kidney, 1alpha(OH)D2 increased TRPV5, calbindin-D28K, and calbindin-D9K mRNA levels by 12 hours. This study indicates that Ca2+ transport proteins, including TRPV5 and TRPV6, are differentially up-regulated by vitamin D compounds.

Keywords:

ECaC1, CaT1, TRPV5, TRPV6, calcium reabsorption, vitamin D, secondary hyperparathyroidism

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