Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1α-hydroxylase knockout mice

Joost G.J. Hoenderop, Helena Chon, Dimitra Gkika, Hans A.R. Bluyssen, Frank C.P. Holstege, Rene St-Arnaud, Branko Braam, Rene J.M. Bindels

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

65 Citaten (Scopus)


Background. Pseudovitamin D deficiency rickets (PDDR) is an autosomal disease, characterized by undetectable levels of 1,25-dihydroxyvitamin D 3 (1,25(OH)2D3), rickets and secondary hyperparathyroidism. Mice in which the 25-hydroxy-vitamin D3- 1α-hydroxylase (1α-OHase) gene was inactivated, presented the same clinical phenotype as patients with PDDR. Methods. cDNA Microarray technology was used on kidneys of 1α-OHase knockout mice to study the expression profile of renal genes in this Ca2+-related disorder. Genome wide molecular events that occur during the rescue of these mice by high dietary Ca2+ intake were studied by the use of 15K cDNA microarray chips. Results. 1α-OHase knockout mice fed a normal Ca2+ diet developed severe hypocalcemia, rickets and died with an average life span of 12 ± 2 weeks. Intriguingly, 1α-OHase-/- mice supplemented with an enriched Ca2+ diet were normocalcemic and not significantly different from wild-type mice. Inactivation of the 1α-OHase gene resulted in a significant regulation of ± 1000 genes, whereas dietary Ca 2+ supplementation of the 1α-OHase-/- mice revealed ± 2000 controlled genes. Interestingly, 557 transcripts were regulated in both situations implicating the involvement in the dietary Ca 2+-mediated rescue mechanism of the 1α-OHase-/- mice. Conspicuous regulated genes encoded for signaling molecules like the PDZ-domain containing protein channel interacting protein, FK binding protein type 4, kinases, and importantly Ca2+ transporting proteins including the Na+-Ca2+ exchanger, calbindin-D 28K and the Ca2+ sensor calmodulin. Conclusion. Dietary Ca2+ intake normalized disturbances in the Ca2+ homeostasis due to vitamin D deficiency that were accompanied by the regulation of a subset of renal genes, including well-known renal Ca2+ transport protein genes, but also genes not previously identified as playing a role in renal Ca2+ handling.

Originele taal-2Engels
Pagina's (van-tot)531-539
Aantal pagina's9
TijdschriftKidney International
Nummer van het tijdschrift2
StatusGepubliceerd - feb. 2004
Extern gepubliceerdJa


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