SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria
SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria
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DOI：
10.1074/jbc.m109.094680
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发表时间：
2010-05-07
影响因子：
4.8
通讯作者：
Boettger, Thomas
中科院分区：
文献类型：
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作者：
Groeger, Nicole;Froehlich, Henning;Boettger, Thomas
离子浓度梯度的维持对于许多器官的功能是必不可少的，包括肾脏、角膜和内耳。角膜中的离子浓度和液体含量由内皮细胞调节，内皮细胞将胶原性无血管角膜基质与前房分开。不能保持正确的离子浓度会导致角膜肿胀和破坏。在内耳中，血管纹负责在内淋巴中产生适当的离子浓度，这对听力至关重要。人类SLC4A11突变导致与角膜营养不良和感知性耳聋相关的综合征。这些症状背后的分子机制知之甚少，阻碍了治疗干预。离子转运蛋白SLC4A11在体外介导钠依赖性硼酸盐转运以及钠离子和氢氧根离子通量。在这里，我们表明，SLC4A11是在角膜的内皮细胞中表达，它可以防止严重的角膜形态变化所造成的增加基质中的氯化钠浓度。在内耳中，SLC4A11位于血管纹下面的纤维细胞中。SLC4A11的缺失导致纤维细胞的形态学变化和耳聋。我们证明，SLC4A11是必不可少的耳蜗电位的产生，但不是在内淋巴钾浓度的调节。在肾脏中，SLC4A11在亨利袢的细降支中表达。SLC4A11是尿浓缩所必需的，这表明SLC4A11参与了将尿浓缩在肾髓质中的逆流增殖。
Maintenance of ion concentration gradients is essential for the function of many organs, including the kidney, the cornea, and the inner ear. Ion concentrations and fluid content in the cornea are regulated by endothelial cells that separate the collagenous avascular corneal stroma from the anterior eye chamber. Failure to maintain correct ion concentrations leads to swelling and destruction of the cornea. In the inner ear, the stria vascularis is responsible for generating proper ion concentrations in the endolymph, which is essential for hearing. Mutations of SLC4A11 in humans lead to syndromes associated with corneal dystrophy and perceptive deafness. The molecular mechanisms underlying these symptoms are poorly understood, impeding therapeutic interventions. The ion transporter SLC4A11 mediates sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions in vitro. Here, we show that SLC4A11 is expressed in the endothelial cells of the cornea where it prevents severe morphological changes of the cornea caused by increased sodium chloride concentrations in the stroma. In the inner ear, SLC4A11 is located in fibrocytes underlying the stria vascularis. Loss of SLC4A11 leads to morphological changes in the fibrocytes and deafness. Wedemonstrate that SLC4A11 is essential for the generation of the endocochlear potential but not for regulation of potassium concentrations in the endolymph. In the kidney, SLC4A11 is expressed in the thin descending limb of Henle loop. SLC4A11 is essential for urinary concentration, suggesting that SLC4A11 participates in the countercurrent multiplication that concentrates urine in the kidney medulla.