Correlation between hyperphosphatemia and type IINa-Pi cotransporter activity in klotho mice
Correlation between hyperphosphatemia and type IINa-Pi cotransporter activity in klotho mice
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DOI：
10.1152/ajprenal.00248.2006
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发表时间：
2007-02-01
影响因子：
4.2
通讯作者：
Miyamoto, Ken-ichi
中科院分区：
文献类型：
--
作者：
Segawa, Hiroko;Yamanaka, Setsuko;Miyamoto, Ken-ichi
最近的研究表明，Klotho蛋白在钙/磷平衡中起着重要作用。本研究的目的是研究Klotho突变(KL/KL)小鼠Na-P-I共转运体的调节。与野生型小鼠相比，KL/KL小鼠表现出高磷血症，血浆1，25(OH)(2)D-3水平升高，肾脏和肠道钠依赖的PI辅助转运体活性增加，IIa型、IIb型和IIc型转运体蛋白水平增加。有趣的是，与野生型小鼠相比，KL/KL小鼠IIa/IIc型转运蛋白mRNA丰度的转录水平显著降低，而IIb型转运蛋白mRNA的转录水平却没有显著下降。此外，KL/KL小鼠的血浆成纤维细胞生长因子23(FGF23)水平是野生型小鼠的150倍。低P-I饮食诱导KL/KL小鼠Klotho蛋白表达，降低血浆FGF23水平，而秋水仙素处理实验显示KL/KL小鼠IIa型转运体异常膜转运。最后，饲喂低P-I饮食导致野生型小鼠根尖膜IIa型Na-P-I共转运蛋白增加，但在KL/KL小鼠中没有。这些结果表明，Klotho小鼠的高磷血症是由于肾脏IIa/IIc转运体的表达和运输失调所致，而不是由于肠道摄取P-I。
Recent studies have demonstrated that klotho protein plays a role in calcium/ phosphate homeostasis. The goal of the present study was to investigate the regulation of Na-P-i cotransporters in klotho mutant (kl/kl) mice. The kl/kl mice displayed hyperphosphatemia, high plasma 1,25(OH)(2)D-3 levels, increased activity of the renal and intestinal sodium-dependent Pi cotransporters, and increased levels of the type IIa, type IIb, and type IIc transporter proteins compared with wild- type mice. Interestingly, transcript levels of the type IIa/type IIc transporter mRNA abundance, but not transcripts levels of type IIb transporter mRNA, were markedly decreased in kl/kl mice compared with wild- type mice. Furthermore, plasma fibroblast growth factor 23 ( FGF23) levels were 150-fold higher in kl/kl mice than in wild- type mice. Feeding of a low-P-i diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice. Finally, feeding of a low-P-i diet resulted in increased type IIa Na-P-i cotransporter protein in the apical membrane in the wild- type mice, but not in kl/kl mice. These results indicate that hyperphosphatemia in klotho mice is due to dysregulation of expression and trafficking of the renal type IIa/IIc transporters rather than to intestinal P-i uptake.