| Abstrakt: |
Disruption of the major renal Na-phosphate (Pi) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brash-border membrane Na-Pi cotransport, hypophosphatemia, and appropriate adaptive increases in renal 25-hydroxyvitamin D3-1α-hydroxylase (1αOHase) 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 1αOHase 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-/-/1αOHase-/- 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-/-/1αOHase-/- 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 1αOHase 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. [ABSTRACT FROM AUTHOR] |
