Modulation of renal Ca ²⁺ transport protein genes by dietary Ca ²⁺ and 1,25‐dihydroxyvitamin D ₃ in 25hydroxyvitamin D ₃ ‐1α‐hydroxylase knockout mice

Pseudovitamin D‐deficiency rickets (PDDR) is an autosomal disease characterized by hyperparathyroidism, rickets, and undetectable levels of 1,25‐dihydroxyvitaminD 3 (1,25(OH) 2 D 3 ). Mice in which the 25hydroxyvitamin D 3 ‐1α‐hydroxylase (1α‐OHase) gene was inactivated presented the same clinical phenotype as patients with PDDR and were used to study renal expression of the epithelial Ca 2+ channel (ECaC1), the calbindins, Na + /Ca 2+ exchanger (NCX1), and Ca 2 + ‐ATPase (PMCA1b). Serum Ca 2+ (1.20±0.05 mM) and mRNA/ protein expression of ECaC1 (41±3%), calbindin‐D 28K (31±2%), calbindin‐D 9K (58±7%), NCX1 (10±2%), PMCA1b (96±4%) were decreased in 1α‐OHase −/− mice compared with 1α‐OHase +/‐ littermates. Feeding these miceaCa 2+ ‐enriched diet normalized serum Ca 2+ levels and expression of Ca 2+ proteins except for calbindin‐D 9K expression. 1,25(OH) 2 D 3 repletion resulted in increased expression of Ca 2+ transport proteins and normalization of serum Ca 2+ levels. Localization of Ca 2+ transport proteins was clearly polarized in which ECaC1 was localized along the apical membrane, calbindin‐D 28K in the cytoplasm, and calbindin‐D 9K along the apical and basolateral membranes, resulting in a comprehensive mechanism facilitating renal transcellular Ca 2+ transport. This study demonstrated that high dietary Ca 2+ intake is an important regulator of the renal Ca 2+ transport proteins in 1,25(OH) 2 D 3 ‐deficient status and thus contributes to the normalization of blood Ca 2+ levels.—Hoenderop, J. G. J., Dardenne, O., van Abel, M., van der Kemp, A. W. C. M., van Os, C. H., St.—Arnaud, R., Bindels, R. J. M. Modulation of renal Ca 2+ transport protein genes by dietary Ca 2+ and 1,25‐dihydroxyvitamin D 3 in 25 hydroxyvitamin D 3 ‐1α‐hydroxylase knockout mice. FASEB J. 16, 1398–1406 (2002)