Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development
Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development
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DOI：
10.1152/ajprenal.00156.2009
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Miyamoto, Ken-ichi
中科院分区：
文献类型：
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作者：
Segawa, Hiroko;Onitsuka, Akemi;Miyamoto, Ken-ichi
Sekawa H, Onitsuka A, Furutani J, Kaneko I, Aranami F, Matsumoto N, Tomoe Y, Kuwahata M, Ito M, Matsumoto M, Li M, Amizuka N, Miyamoto K. 小鼠中的 Npt2a 和 Npt2c 在无机磷酸盐代谢和骨骼发育中发挥独特的协同作用。 Am J Physiol Renal Physiol 297：F671-F678，2009。首次发布于 2009 年 7 月 1 日； doi:10.1152/ajprenal.00156.2009.-遗传性低磷血症性佝偻病伴高钙尿症 (HHRH) 是一种罕见的常染色体隐性遗传性疾病，其特征为低磷血症、身材矮小、佝偻病和/或骨软化症以及继发性吸收性高钙尿症。 HHRH 是由钠依赖性磷酸盐转运蛋白 (NaPi-IIc/Npt2c/NPT2c) 缺陷引起的，人们认为该蛋白在成年小鼠肾磷酸盐 (P-i) 重吸收中只起很小的作用。事实上，当维持正常磷酸盐含量的饮食时，Npt2c (Npt2c(-/-)) 无效的小鼠没有显示出肾磷酸盐消耗的证据。为了深入了解 Npt2a 和 Npt2c 的相对重要性，我们现在研究了 Npt2a(+/+) Npt2c(+/+)、Npt2a(+/-) Npt2c(-/-) 和 Npt2a(-/-) Npt2c(-/-) 双敲除 (DKO)。 DKO 小鼠表现出严重的低磷血症、高钙尿症和佝偻病。这些发现不同于 Npt2a KO 小鼠中的结果，Npt2a KO 小鼠中仅显示出轻微的磷酸盐和骨表型，并且随着时间的推移而改善，并且与 Npt2c KO 小鼠中的发现不同，Npt2c KO 小鼠中的磷酸盐稳态调节没有明显的异常。由于 Npt2a 和 Npt2c 的非冗余作用，DKO 动物的肾小管细胞刷状缘膜中的 P-i 转运活性比单基因消融的小鼠表现出更明显的降低。断奶后的高 P-i 饮食可恢复 DKO 小鼠的血浆磷酸盐水平和骨表型。因此，我们的研究结果表明，在小鼠中，Npt2a 和 Npt2c 在血浆 P-i 和骨矿化的调节中具有独立的作用。
Segawa H, Onitsuka A, Furutani J, Kaneko I, Aranami F, Matsumoto N, Tomoe Y, Kuwahata M, Ito M, Matsumoto M, Li M, Amizuka N, Miyamoto K. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. Am J Physiol Renal Physiol 297: F671-F678,2009. First published July 1, 2009; doi:10.1152/ajprenal.00156.2009.-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 nonreddundant 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.