Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis
Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis
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DOI：
10.1073/pnas.1203834109
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发表时间：
2012-08-28
影响因子：
11.1
通讯作者：
Mueller, Dominik
中科院分区：
文献类型：
--
作者：
Breiderhoff, Tilman;Himmerkus, Nina;Mueller, Dominik
在肾脏中，紧密连接蛋白有助于细胞旁离子转运的片段特异性选择性和渗透性。在亨利氏袢的粗升支（TAL）中，氯离子通过细胞重吸收，而钠离子的重吸收则通过细胞和细胞旁途径。TAL盐转运维持肾脏的浓缩能力，并产生驱动钙和镁重吸收的跨上皮电压。因此，TAL离子转运的功能性强烈依赖于细胞旁途径的性质。为了阐明紧密连接蛋白claudin-10在TAL功能中的作用，我们产生了在该片段中缺失Cldn 10的小鼠。我们表明，claudin-10决定细胞旁钠渗透性，其损失导致高镁血症和肾钙质沉着症。在claudin-10缺陷小鼠的离体灌注TAL小管中，钠的细胞旁渗透性降低，钙和镁的相对渗透性增加。此外，呋塞米耐受的跨上皮电压增加，导致钙和镁从细胞旁钠转运转变为细胞旁高吸收。这些数据确定了密封蛋白-10作为控制TAL中阳离子选择性和转运的关键因子，并且该途径的缺陷是肾钙质沉着症的原因。
In the kidney, tight junction proteins contribute to segment specific selectivity and permeability of paracellular ion transport. In the thick ascending limb (TAL) of Henle's loop, chloride is reabsorbed transcellularly, whereas sodium reabsorption takes transcellular and paracellular routes. TAL salt transport maintains the concentrating ability of the kidney and generates a transepithelial voltage that drives the reabsorption of calcium and magnesium. Thus, functionality of TAL ion transport depends strongly on the properties of the paracellular pathway. To elucidate the role of the tight junction protein claudin-10 in TAL function, we generated mice with a deletion of Cldn10 in this segment. We show that claudin-10 determines paracellular sodium permeability, and that its loss leads to hypermagnesemia and nephrocalcinosis. In isolated perfused TAL tubules of claudin-10-deficient mice, paracellular permeability of sodium is decreased, and the relative permeability of calcium and magnesium is increased. Moreover, furosemide-inhibitable transepithelial voltage is increased, leading to a shift from paracellular sodium transport to paracellular hyperabsorption of calcium and magnesium. These data identify claudin-10 as a key factor in control of cation selectivity and transport in the TAL, and deficiency in this pathway as a cause of nephrocalcinosis.