1α-Hydroxylase gene ablation and Pisupplementation inhibit renal calcification in mice homozygous for the disruptedNpt2agene

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Abstract
Disruption of the major renal Na-phosphate (Pi) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brush-border membrane Na-Picotransport, 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 1α OHase gene ablation and long-term Pisupplementation on urinary Ca excretion and renal calcification by microcomputed tomography. We show that the urinary Ca/creatinine ratio is significantly decreased in Npt2-/-/1α OHase-/-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-/-/1α OHase-/-mice compared with that in Npt2-/-mice. In Npt2-/-mice derived from dams fed a 1% Pidiet 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 1α OHase gene ablation and Pisupplementation 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.