Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14241-6. doi: 10.1073/pnas.1203834109. Epub 2012 Aug 13.
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.
在肾脏中，紧密连接蛋白有助于形成特定于节段的细胞旁离子转运选择性和通透性。在亨利氏袢的升支粗段 (TAL) 中，氯离子通过细胞旁途径进行重吸收，而钠离子的重吸收则通过细胞内和细胞旁途径进行。TAL 的盐转运维持了肾脏的浓缩能力，并产生跨上皮电压，从而驱动钙和镁的重吸收。因此，TAL 离子转运的功能强烈依赖于细胞旁途径的特性。为了阐明紧密连接蛋白 Claudin-10 在 TAL 功能中的作用，我们在该节段生成了 Claudin-10 缺失的小鼠。我们表明 Claudin-10 决定了细胞旁钠离子通透性，其缺失导致高镁血症和肾钙质沉着症。在 Claudin-10 缺陷型小鼠的分离灌注 TAL 小管中，钠离子的细胞旁通透性降低，而钙和镁的相对通透性增加。此外，呋塞米抑制的跨上皮电压增加，导致从细胞旁钠离子转运转变为细胞旁钙和镁的过度吸收。这些数据表明 Claudin-10 是控制 TAL 中阳离子选择性和转运的关键因素，而该途径的缺陷是肾钙质沉着症的原因。
