Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium
Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium
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DOI：
10.1074/jbc.m700632200
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发表时间：
2007-06-08
影响因子：
4.8
通讯作者：
Goodenough, Daniel A.
中科院分区：
文献类型：
--
作者：
Hou, Jianghui;Shan, Qixian;Goodenough, Daniel A.
紧密连接在介导肾脏细胞旁离子重吸收中发挥关键作用。家族性低镁血症伴高钙尿症和肾钙质沉着症 (FHHNC) 是一种由紧密连接蛋白claudin-16 突变引起的人类疾病。然而，肾脏处理镁及其功能障碍导致 FHHNC 的分子机制尚不清楚。在这里，我们证明claudin-16在维持肾单位粗升肢的细胞旁阳离子选择性方面发挥着关键作用。利用 RNA 干扰，我们生成了claudin-16 缺陷小鼠模型。 Claudin-16 敲除 (KD) 小鼠表现出镁和钙的慢性肾消耗并发展为肾钙质沉着症。我们的数据表明，claudin-16 形成非选择性的细胞旁阳离子通道，而不是先前提出的选择性 Mg2+ /Ca2+ 通道。我们的研究强调了紧密连接在肾脏控制离子稳态中的关键重要性，并为 FHHNC 的发病机制提供了答案。我们预计我们的研究将成为对肾功能中紧密连接蛋白进行更复杂的体内分析的起点。此外，紧密连接蛋白可能是电解质紊乱药物开发的主要目标。
Tight junctions play a key role in mediating paracellular ion reabsorption in the kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a human disorder caused by mutations in the tight junction protein claudin-16. However, the molecular mechanisms underlining the renal handling of magnesium and its dysfunction causing FHHNC are unknown. Here we show that claudin-16 plays a key role in maintaining the paracellular cation selectivity of the thick ascending limbs of the nephron. Using RNA interference, we have generated claudin-16-deficient mouse models. Claudin-16 knock-down (KD) mice exhibit chronic renal wasting of magnesium and calcium and develop renal nephrocalcinosis. Our data suggest that claudin-16 forms a non-selective paracellular cation channel, rather than a selective Mg2+ /Ca2+ channel as previously proposed. Our study highlights the pivotal importance of the tight junction in renal control of ion homeostasis and provides answer to the pathogenesis of FHHNC. We anticipate our study to be a starting point for more sophisticated in vivo analysis of tight junction proteins in renal functions. Furthermore, tight junction proteins could be major targets of drug development for electrolyte disorders.