Hou Jianghui
Renal Division, Washington University in St. louis, St. Louis, Missouri, USA.
Curr Opin Nephrol Hypertens. 2016 Sep;25(5):424-8. doi: 10.1097/MNH.0000000000000253.
The paracellular pathway through the tight junction provides an important route for chloride reabsorption in the collecting duct of the kidney. This review describes recent findings of how defects in paracellular chloride permeation pathway may cause kidney diseases and how such a pathway may be regulated to maintain normal chloride homeostasis.
The tight junction in the collecting duct expresses two important claudin genes - claudin-4 and claudin-8. Transgenic knockout of either claudin gene causes hypotension, hypochloremia, and metabolic alkalosis in experimental animals. The claudin-4 mediated chloride permeability can be regulated by a protease endogenously expressed by the collecting duct cell - channel-activating protease 1. Channel-activating protease 1 regulates the intercellular interaction of claudin-4 and its membrane stability. Kelch-like 3, previously identified as a causal gene for Gordon's syndrome, also known as pseudohypoaldosteronism II, directly interacts with claudin-8 and regulates its ubiquitination and degradation. The dominant pseudohypoaldosteronism-II mutation (R528H) in Kelch-like 3 abolishes claudin-8 binding, ubiquitination, and degradation.
The paracellular chloride permeation pathway in the kidney is an important but understudied area in nephrology. It plays vital roles in renal salt handling and regulation of extracellular fluid volume and blood pressure. Two claudin proteins, claudin-4 and claudin-8, contribute to the function of this paracellular pathway. Deletion of either claudin protein from the collecting duct causes renal chloride reabsorption defects and low blood pressure. Claudins can be regulated on posttranslational levels by several mechanisms involving protease and ubiquitin ligase. Deregulation of claudins may cause human hypertension as exemplified in the Gordon's syndrome.
通过紧密连接的细胞旁途径是肾脏集合管中氯离子重吸收的重要途径。本综述描述了关于细胞旁氯离子渗透途径缺陷如何导致肾脏疾病以及该途径如何被调节以维持正常氯离子稳态的最新研究发现。
集合管中的紧密连接表达两个重要的闭合蛋白基因——闭合蛋白 -4 和闭合蛋白 -8。任一闭合蛋白基因的转基因敲除都会在实验动物中导致低血压、低氯血症和代谢性碱中毒。闭合蛋白 -4 介导的氯离子通透性可由集合管细胞内源性表达的一种蛋白酶——通道激活蛋白酶 1 调节。通道激活蛋白酶 1 调节闭合蛋白 -4 的细胞间相互作用及其膜稳定性。 Kelch 样蛋白 3，先前被鉴定为戈登综合征（也称为假性醛固酮减少症 II 型）的致病基因，直接与闭合蛋白 -8 相互作用并调节其泛素化和降解。 Kelch 样蛋白 3 中的显性假性醛固酮减少症 II 型突变（R528H）消除了与闭合蛋白 -8 的结合、泛素化和降解。
肾脏中的细胞旁氯离子渗透途径是肾脏病学中一个重要但研究不足的领域。它在肾脏盐处理以及细胞外液量和血压调节中起着至关重要的作用。两种闭合蛋白，闭合蛋白 -4 和闭合蛋白 -8，对该细胞旁途径的功能有贡献。从集合管中缺失任一闭合蛋白都会导致肾脏氯离子重吸收缺陷和低血压。闭合蛋白可通过涉及蛋白酶和泛素连接酶的多种机制在翻译后水平受到调节。如在戈登综合征中所示，闭合蛋白失调可能导致人类高血压。
