Homeostasis of inorganic phosphate (Pi) is achieved by equilibrating renal reabsorption and intestinal absorption. Renal reabsorption of Pi takes place preferentially in the proximal tubule and is mediated by Na/Pi-cotransporters SLC34A1/NaPi-IIa, SLC34A3/NaPi-IIc and SLC20A2/Pit-2. In mouse NaPi-IIa plays a major quantitative role, whereas the contribution of NaPi-IIc was considered to be restricted to young animals. Recent data suggest a correlation between mutations in the NaPi-IIc gene with hypophosphatemic syndromes in humans.

To investigate the renal contribution of NaPi-IIc, we generated a renal specific inducible NaPi-IIc mouse model. Mice harboring both NaPi-IIc alleles flanked by loxP sites (NaPi-IIc^fl/fl) were bred with Pax8rtTA/LC1 animals (kindly provided by Dr.Koester, University of Heidelberg) in which the renal expression of Cre recombinase can be induced by doxycycline. Further mating resulted in homozygous (NaPi-IIc^fl/fl) and heterozygous mutants (NaPi-IIc^fl/+) as well as wild type (NaPi-IIc^+/+) mice which expressed Pax8 and Cre.

Three to four week old mice were treated for 10 days with drinking water supplemented with either sucrose alone (2%) or in combination with doxycycline. Administration of doxycycline led to full ablation of NaPi-IIc mRNA and protein in NaPi-IIc^fl/fl and no changes in NaPi-IIc^+/+ mice. The absence of NaPi-IIc in NaPi-IIc^fl/fl mice did not result in changes on uptake of Pi in renal BBMV`s. The serum and urinary excretion of Pi were no different in NaPi-IIc^fl/fl and NaPi-IIc^+/+ mice. Parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) also remain unchanged. The abundance of NaPi-IIa in the renal BBM was similar between NaPi-IIc^fl/fl and NaPi-IIc^+/+ mice. In contrast to a reported constitutive knock out mouse model of NaPi-IIc, the urinary and circulating levels of Ca⁺⁺ remained normal in NaPi-IIc^fl/fl mice. Moreover, the renal expression of mRNAs of both the 1α-hydroxylase and the 24-hydroxylase were also similar.

In conclusion, we have generated a renal-specific and inducible knockout mouse model of NaPi-IIc.Our findings suggest that the absence of NaPi-IIc does not change the homeostatic function of the kidney in terms of Pi handling. However, and unlike in the constitutive mutants, the renal-specific ablation of the NaPi-IIc does not alter the homeostasis of Ca⁺⁺, suggesting that extra-renal expression of the NaPi-IIc may be responsible for the cross-talk of NaPi-IIc with the metabolism of Ca⁺⁺.