Ezrin, a membrane cytoskeletal cross-linker, is essential for the regulation of phosphate and calcium homeostasis
Ezrin, a membrane cytoskeletal cross-linker, is essential for the regulation of phosphate and calcium homeostasis
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DOI：
10.1038/ki.2012.308
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发表时间：
2013-01-01
影响因子：
19.6
通讯作者：
Asano, Shinji
中科院分区：
文献类型：
--
作者：
Hatano, Ryo;Fuji, Elko;Asano, Shinji
埃兹蛋白将质膜蛋白与肌动蛋白细胞骨架交联。在肾脏中，埃兹蛋白主要定位于近端小管的刷状缘膜，具有支架蛋白，Na+/H+交换调节因子（NHERF）1。NHERF 1与钠/磷酸盐协同转运蛋白Npt 2a相互作用。小鼠中NHERF 1或Npt 2a的缺陷导致低磷酸盐血症。在这里，我们研究了ezrin在肾磷酸盐重吸收中的生理作用，使用ezrin敲低小鼠（Vil 2）。这些小鼠表现出低磷酸盐血症、低钙血症和骨软化。血浆磷酸盐浓度降低归因于尿磷酸盐重吸收缺陷。免疫荧光和免疫印迹表明，在敲除小鼠的近端小管顶膜处，肾Npt 2a和NHERF 1表达显著降低。另一方面，在Vil 2小鼠中未发现尿钙损失。血浆磷酸盐水平降低后，血浆中1，25-二羟维生素D浓度升高，敲除小鼠十二指肠中维生素D依赖性TRPV 6钙通道的mRNA显著增加。然而，TRPV 6在顶膜的表达显著降低。此外，胫骨骨矿物质密度显着较低的成年和年轻的Vil 2小鼠。这些结果表明，ezrin是需要在体内调节全身磷酸盐和钙稳态。Kidney International（2012）83，41-49; doi：10.1038/ki.2012.308; 2012年8月15日在线发表
Ezrin cross-links plasma membrane proteins with the actin cytoskeleton. In the kidney, ezrin mainly localizes at the brush border membrane of proximal tubules with the scaffolding protein, Na+/H+ exchanger regulatory factor (NHERF) 1. NHERF1 interacts with the sodium/phosphate cotransporter, Npt2a. Defects in NHERF1 or Npt2a in mice cause hypophosphatemia. Here we studied the physiological role of ezrin in renal phosphate reabsorption using ezrin knockdown mice (Vil2). These mice exhibit hypophosphatemia, hypocalcemia, and osteomalacia. The reduced plasma phosphate concentrations were ascribed to defects in urinary phosphate reabsorption. Immunofluorescence and immunoblotting indicated a marked reduction in renal Npt2a and NHERF1 expression at the apical membrane of proximal tubules in the knockdown mice. On the other hand, urinary loss of calcium was not found in Vil2 mice. Plasma concentrations of 1,25-dihydroxyvitamin D were elevated following reduced plasma phosphate levels, and mRNA of the vitamin D-dependent TRPV6 calcium channel were significantly increased in the duodenum of knockdown mice. Expression of TRPV6 at the apical membrane, however, was significantly decreased. Furthermore, tibial bone mineral density was significantly lower in both the adult and young Vil2 mice. These results suggest that ezrin is required for the regulation of systemic phosphate and calcium homeostasis in vivo. Kidney International (2012) 83, 41-49; doi:10.1038/ki.2012.308; published online 15 August 2012