1alpha-Hydroxylase gene ablation and Pi supplementation inhibit renal calcification in mice homozygous for the disrupted Npt2a gene.
Disruption of the major renal Na-phosphate (Pi) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brush-border membrane Na-Pi cotransport, hypophosphatemia, and appropriate adaptive increases in renal 25-hydroxyvitamin D3-1alpha-hydroxylase (1alphaOHase) 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 1alphaOHase gene ablation and long-term Pi supplementation on urinary Ca excretion and renal calcification by microcomputed tomography. We show that the urinary Ca/creatinine ratio is significantly decreased in Npt2-/-/1alphaOHase-/- 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-/-/1alphaOHase-/- mice compared with that in Npt2-/- mice. In Npt2-/- mice derived from dams fed a 1% Pi 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 1alphaOHase gene ablation and Pi 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.
Tenenhouse
Harriet S
HS
McGill Univ.-Montreal Children's Hospital Research Institute, 4060 Ste-Cathe ine St. West, Montreal, Quebec, Canada H3Z 2Z3. harriet.tenenhouse@mcgill.ca
Gauthier
Claude
C
Chau
Hien
H
St-Arnaud
René
R
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000818:Animals; D002114:Calcinosis / Q000503:physiopathology; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood / Q000652:urine; D005260:Female; D006720:Homozygote; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009397:Nephrocalcinosis / Q000473:pathology / Q000503:physiopathology*; D016226:Phosphorus, Dietary / Q000494:pharmacology; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters / Q000235:genetics*
D016226:Phosphorus, Dietary; C493549:Slc17a2 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium