Type IIc Sodium–Dependent Phosphate Transporter Regulates Calcium Metabolism

Abstract

Primary renal inorganic phosphate (Pi) wasting leads to hypophosphatemia, which is associated with skeletal mineralization defects. In humans, mutations in the gene encoding the type IIc sodiumdependent phosphate transporter lead to hereditary hypophophatemic rickets with hypercalciuria, but whether Pi wasting directly causes the bone disorder is unknown. Here, we generated Npt2c-null mice to define the contribution of Npt2c to Pi homeostasis and to bone abnormalities. Homozygous mutants (Npt2c Ϫ/Ϫ ) exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D 3 levels, but they did not develop hypophosphatemia, hyperphosphaturia, renal calcification, rickets, or osteomalacia. The increased levels of 1,25-dihydroxyvitamin D 3 in Npt2c Ϫ/Ϫ mice compared with age-matched Npt2c ϩ/ϩ mice may be the result of reduced catabolism, because we observed significantly reduced expression of renal 25-hydroxyvitamin D-24-hydroxylase mRNA but no change in 1␣-hydroxylase mRNA levels. Enhanced intestinal absorption of calcium (Ca) contributed to the hypercalcemia and increased urinary Ca excretion. Furthermore, plasma levels of the phosphaturic protein fibroblast growth factor 23 were significantly decreased in Npt2c Ϫ/Ϫ mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c ϩ/ϩ , Npt2c ϩ/Ϫ , and Npt2c Ϫ/Ϫ mice.In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis. 20: 104 -113, 200920: 104 -113, . doi: 10.1681 Inorganic phosphate (Pi) is an essential nutrient in terms of both cellular metabolism and skeletal mineralization. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi needs. Up to 70% of filtered Pi is reabsorbed in the proximal tubule in which sodium (Na)-dependent Pi transport systems in the brush border membrane (BBM) mediated the rate-limiting step in the overall Pi reabsorptive process. J Am Soc Nephrol

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

“…In contrast, Na + -dependent Pi-uptake into BBMV was very low and remained unchanged in NaPi-IIa -/-mice whatever the diet. The remaining activity in knock-out BBM is approximately reduced to 30 % under chronic high phosphate diet which is similar to what was described earlier [50,56]. This result indicates that NaPi-IIc and Pit-2 transport activities are low in mice and may already be maximally stimulated in NaPi-IIa deficient mice as compensatory mechanism.…”

NaPi-IIa interacting proteins and regulation of renal reabsorption of phosphate

“…These findings, together with the lack of phenotype of NaPi-IIc deficient mice regarding P i balance [26], indicate that NaPi-IIa is the major cotransporter in the murine kidney. Ablation of both NaPi-IIa [7] and NaPi-IIc [26] results in hypercalcemia and hypercalciuria; as mentioned above, these changes are probably due to a 1,25(OH) 2 D 3 -induced upregulation of intestinal Ca ++ absorption. While disregulation of Ca ++ homeostasis results in the formation of renal stones in NaPi-IIa deficient mice [7], the absence of NaPi-IIc does not seem to increase renal mineral deposition [26].…”

“…Ablation of both NaPi-IIa [7] and NaPi-IIc [26] results in hypercalcemia and hypercalciuria; as mentioned above, these changes are probably due to a 1,25(OH) 2 D 3 -induced upregulation of intestinal Ca ++ absorption. While disregulation of Ca ++ homeostasis results in the formation of renal stones in NaPi-IIa deficient mice [7], the absence of NaPi-IIc does not seem to increase renal mineral deposition [26]. In humans, mutations of NaPi-IIa have been reported in patients with hypophosphatemic syndromes [21]; however, it is no clear whether these mutations alone can account for the hypophosphatemic state [31].…”

“…NaPi-IIa deficient mice are hypophosphatemic due to an increased urinary excretion of P i despite a heavy upregulation of NaPi-IIc [2]. These findings, together with the lack of phenotype of NaPi-IIc deficient mice regarding P i balance [26], indicate that NaPi-IIa is the major cotransporter in the murine kidney. Ablation of both NaPi-IIa [7] and NaPi-IIc [26] results in hypercalcemia and hypercalciuria; as mentioned above, these changes are probably due to a 1,25(OH) 2 D 3 -induced upregulation of intestinal Ca ++ absorption.…”

The SLC34 family of sodium-dependent phosphate transporters

“…During phosphate depletion, NaPi-IIc protein is also detected in the early proximal tubule of superficial nephrons [24,112,121]. NaPi-IIc may also be expressed in bone but its function there has not been elucidated [125].…”