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This Article Full Text Full Text (PDF) All Versions of this Article: 286/4/F675    most recent 00362.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Tenenhouse, H. S. Articles by St.-Arnaud, R. Search for Related Content PubMed PubMed Citation Articles by Tenenhouse, H. S. Articles by St.-Arnaud, R.

1-Hydroxylase gene ablation and P_i supplementation inhibit renal calcification in mice homozygous for the disrupted Npt2a gene

Departments of ¹Human Genetics, ²Pediatrics, ⁴Biology, and ⁵Surgery, McGill University, ³The McGill University-Montreal Children's Hospital Research Institute, Montreal H3Z 2Z3, and ⁶Shriners Hospital for Children, Montreal, Quebec, Canada H3G 1A6

Submitted 15 October 2003 ; accepted in final form 1 December 2003

Disruption of the major renal Na-phosphate (P_i) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brush-border membrane Na-P_i cotransport, hypophosphatemia, and appropriate adaptive increases in renal 25-hydroxyvitamin D₃-1-hydroxylase (1OHase) activity and the serum concentration of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D]. The latter is associated with increased intestinal Ca absorption, hypercalcemia, hypercalciuria, and renal calcification in Npt2^-/- mice. To determine the contribution of elevated serum 1,25(OH)₂D levels to the development of hypercalciuria and nephrocalcinosis in Npt2^-/- mice, we examined the effects of 1OHase gene ablation and long-term P_i supplementation on urinary Ca excretion and renal calcification by microcomputed tomography. We show that the urinary Ca/creatinine ratio is significantly decreased in Npt2^-/-/1OHase^-/- mice compared with Npt2^-/- mice. In addition, renal calcification, determined by estimating the calcified volume to total renal volume (CV/TV), is reduced by 80% in Npt2^-/-/1OHase^-/- mice compared with that in Npt2^-/- mice. In Npt2^-/- mice derived from dams fed a 1% P_i diet and maintained on the same diet, we observed a significant decrease in urinary Ca/creatinine that was also associated with 80% reduction in CV/TV when compared with counterparts fed a 0.6% diet. Taken together, the present data demonstrate that both 1OHase gene ablation and P_i supplementation inhibit renal calcification in Npt2^-/- mice and that 1,25(OH)₂D is essential for the development of hypercalciuria and nephrocalcinosis in the mutant strain.

phosphate wasting; hypophosphatemia; hypercalciuria; nephrocalcinosis; 1,25-dihydroxyvitamin D

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