Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities
Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities
复制标题
DOI：
10.1073/pnas.95.9.5372
复制
发表时间：
1998-04-28
影响因子：
11.1
通讯作者：
Tenenhouse, HS
中科院分区：
文献类型：
--
作者：
Beck, L;Karaplis, AC;Tenenhouse, HS
Npt2编码肾特异性的刷状边界膜Na+-磷酸（P-i）共转运蛋白，该蛋白在近端小管中表达，过滤后的大部分P-i被重吸收。通过靶向诱变产生Npt2基因缺陷的小鼠，以确定Npt2在总体维持P-i稳态中的作用，确定其对骨骼发育的影响，并阐明其与人类肾脏P-i重吸收常染色体疾病的关系。纯合突变体（Npt2(-/-)）表现为尿P-i排泄增加，低磷血症，血清1,25-二羟基维生素D浓度适当升高，伴有高钙血症、高钙血症和血清甲状旁腺激素水平降低，血清碱性磷酸酶活性增加。这些生化特征是遗传性低磷血症佝偻病合并高钙尿症（HHRH）患者的典型特征，HHRH是一种肾磷再吸收的孟德尔疾病。然而;与HHRH患者不同，Npt2（-/-）小鼠没有佝偻病或骨软化症。断奶时，Npt2（-/-）小鼠骨小梁发育不良，继发性骨化迟缓，但随着年龄的增长，骨骼表型发生戏剧性逆转并最终过度补偿。我们的研究结果表明，Npt2是P-i稳态的主要调节因子，是正常骨骼发育所必需的。
Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (P-i) cotransporter that is expressed in the proximal tubule where the bulk of filtered P-i is reabsorbed. Mice deficient in the Npt2 gene mere generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of P-i homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal P-i reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhibit increased urinary P-i excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal P-i reabsorption. However; unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia, At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype, Our findings demonstrate that Npt2 is a major regulator of P-i homeostasis and necessary for normal skeletal development.