Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development

Abstract

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessively inherited disorder, characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH is caused by a defect in the sodium-dependent phosphate transporter (NaPi-IIc/Npt2c/NPT2c), which was thought to have only a minor role in renal phosphate (P(i)) reabsorption in adult mice. In fact, mice that are null for Npt2c (Npt2c(-/-)) show no evidence for renal phosphate wasting when maintained on a diet with a normal phosphate content. To obtain insights and the relative importance of Npt2a and Npt2c, we now studied Npt2a(-/-)Npt2c(+/+), Npt2a(+/-)Npt2c(-/-), and Npt2a(-/-)Npt2c(-/-) double-knockout (DKO). DKO mice exhibited severe hypophosphatemia, hypercalciuria, and rickets. These findings are different from those in Npt2a KO mice that show only a mild phosphate and bone phenotype that improve over time and from the findings in Npt2c KO mice that show no apparent abnormality in the regulation of phosphate homeostasis. Because of the nonredundant roles of Npt2a and Npt2c, DKO animals showed a more pronounced reduction in P(i) transport activity in the brush-border membrane of renal tubular cells than that in the mice with the single-gene ablations. A high-P(i) diet after weaning rescued plasma phosphate levels and the bone phenotype in DKO mice. Our findings thus showed in mice that Npt2a and Npt2c have independent roles in the regulation of plasma P(i) and bone mineralization.

Renal Control of Calcium, Phosphate, and Magnesium Homeostasis

“…PiT-2 (SLC20A2) is encoded by a member of the SLC20 family (28). Within the proximal tubule in rats and mice, the abundance of Npt2a gradually decreases along the proximal tubule, whereas Npt2c and PiT-2 are expressed mainly in the first (S1) segment (29). Work from knockout studies in rodents has shown that in mice, Npt2a is responsible for the majority (approximately 70%) of the renal regulation of phosphate transport (29).…”

Clinical Consequences of Mutations in Sodium Phosphate Cotransporters

“…A variety of mutations including compound heterozygous deletion and missense mutations in Npt2c have been identified in other families with HHRH. Pi transport studies in a Xenopus oocyte system revealed that NPT2c gene mutations significantly decreased Na + -dependent Pi transport activity (88). These observations suggest that NPT2c has an important role in renal Pi reabsorption and bone mineralization, and that it may be a key determinant of plasma Pi concentration in humans.…”

“…This autosomal recessive disorder is characterized by hypophosphatemia, renal Pi wasting, increased serum 1,25 dihydroxyvitamin D 3 concentrations, hypercalciuria, rickets, and osteomalacia (83)(84)(85)(86)(87)(88). A genomewide scan combined with homozygosity mapping using DNA from 10 patients with HHRH (83) identified a single nucleotide deletion (c.228delC) in all individuals in the initial cohort affected with HHRH.…”

Of Men and Mice

“…1,2,4 The absence of NaPi-IIa induces massive renal losses of phosphate, leading to hypophosphatemia, rickets, and hypercalciuria. Hypercalciuria is the consequence of elevated vitamin D 3 levels stimulating intestinal calcium hyperabsorption and subsequent renal excretion.…”

“…7 Deletion of NaPi-IIc (Slc34a3) in mice is fully compensated because no hyperphosphaturia or hypophosphatemia occurs. 4 The role of these transporters in human kidney is much less clear. Missense mutations and large deletions in the NaPi-IIc (SLC34A3) gene in patients with hereditary hypophosphatemic rickets with hypercalciuria indicate that NaPi-IIc is critical for determining serum phosphate levels and urinary phosphate excretion.…”