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

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 D-3-1alpha-hydroxylase (1alphaOHase) activity and the serum concentration of 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D]. 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)(2)D levels to the development of hypercalciuria and nephrocalcinosis in Npt2(-/-) mice, we examined the effects of 1alphaOHase 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(-/-)/ 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 similar to80% in Npt2(-/-)/ 1alphaOHase(-/-) 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 similar to 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 P-i supplementation inhibit renal calcification in Npt2(-/-) mice and that 1,25(OH)(2)D is essential for the development of hypercalciuria and nephrocalcinosis in the mutant strain.