Segawa Hiroko, Onitsuka Akemi, Kuwahata Masashi, Hanabusa Etsuyo, Furutani Junya, Kaneko Ichiro, Tomoe Yuka, Aranami Fumito, Matsumoto Natsuki, Ito Mikiko, Matsumoto Mitsuru, Li Minqi, Amizuka Norio, Miyamoto Ken-Ichi
Department of Molecular Nutrition, Institution of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan.
J Am Soc Nephrol. 2009 Jan;20(1):104-13. doi: 10.1681/ASN.2008020177. Epub 2008 Dec 3.
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.
原发性肾性无机磷酸盐（Pi）流失会导致低磷血症，这与骨骼矿化缺陷有关。在人类中，编码IIc型钠依赖性磷酸盐转运体的基因突变会导致伴有高钙尿症的遗传性低磷性佝偻病，但Pi流失是否直接导致骨骼疾病尚不清楚。在这里，我们生成了Npt2c基因敲除小鼠，以确定Npt2c对Pi稳态和骨骼异常的作用。纯合突变体（Npt2c(-/-)）表现出高钙血症、高钙尿症和血浆1,25-二羟维生素D(3)水平升高，但它们并未出现低磷血症、高磷尿症、肾钙化、佝偻病或骨软化症。与年龄匹配的Npt2c(+/+)小鼠相比，Npt2c(-/-)小鼠中1,25-二羟维生素D(3)水平升高可能是分解代谢减少的结果，因为我们观察到肾25-羟维生素D-24-羟化酶mRNA表达显著降低，但1α-羟化酶mRNA水平没有变化。肠道对钙（Ca）吸收的增强导致了高钙血症和尿钙排泄增加。此外，Npt2c(-/-)小鼠中促磷排泄蛋白成纤维细胞生长因子23的血浆水平显著降低。然而，Npt2c(+/+)、Npt2c(+/-)和Npt2c(-/-)小鼠肾刷状缘膜上的钠依赖性Pi共转运没有差异。总之，这些数据表明Npt2c通过部分调节维生素D/成纤维细胞生长因子23轴来维持正常的钙代谢。
