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 sodium-dependent 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(-/-)) 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(-/-) mice compared with age-matched Npt2c(+/+) 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 1alpha-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(-/-) mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c(+/+), Npt2c(+/-), and Npt2c(-/-) mice. In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis.

• Authors: Hiroko Segawa, Akemi Onitsuka, Masashi Kuwahata, Etsuyo Hanabusa, Junya Furutani, Ichiro Kaneko, Yuka Tomoe, Fumito Aranami, Natsuki Matsumoto, Mikiko Ito, Mitsuru Matsumoto, Minqi Li, Norio Amizuka, Ken-Ichi Miyamoto
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 20 Issue 1 Pg. 104-13 (Jan 2009) ISSN: 1533-3450 [Electronic] United States
• PMID: 19056871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calbindins
• Calcium Channels
• Phosphates
• RNA, Messenger
• S100 Calcium Binding Protein G
• Slc34a3 protein, mouse
• Sodium-Phosphate Cotransporter Proteins, Type IIc
• TRPV Cation Channels
• Trpv5 protein, mouse
• Trpv6 protein, mouse
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• Calcium

Topics

• Animals
• Biological Transport
• Bone and Bones (chemistry, pathology)
• Calbindins
• Calcium (metabolism)
• Calcium Channels (genetics)
• Fasting (metabolism)
• Female
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphates (metabolism)
• RNA, Messenger (analysis)
• S100 Calcium Binding Protein G (genetics)
• Sodium-Phosphate Cotransporter Proteins, Type IIc (genetics, physiology)
• TRPV Cation Channels (genetics)