Renal Division, Washington University, St. Louis, MO, USA.
Organogenesis. 2012 Jan-Mar;8(1):1-9. doi: 10.4161/org.19808. Epub 2012 Jan 1.
The physiology of paracellular permeation of ions and solutes in the kidney is pivotally important but poorly understood. Claudins are the key components of the paracellular pathway. Defects in claudin function result in a broad range of renal diseases, including hypomagnesemia, hypercalciuria and nephrolithiasis. This review describes recent findings on the physiological function of claudins underlying paracellular transport mechanisms with a focus on renal Ca(2+) handling. We have uncovered a molecular mechanism underlying paracellular Ca(2+) transport in the thick ascending limb of Henle (TAL) that involves the functional interplay of three important claudin genes: claudin-14, -16 and -19, all of which are associated with human kidney diseases with hypercalciuria, nephrolithiasis and bone mineral loss. The Ca(2+) sensing receptor (CaSR) signaling in the kidney has long been a mystery. By analyzing small non-coding RNA molecules in the kidney, we have uncovered a novel microRNA based signaling pathway downstream of CaSR that directly regulates claudin-14 gene expression and establishes the claudin-14 molecule as a key regulator for renal Ca(2+) homeostasis. The molecular cascade of CaSR-microRNAs-claudins forms a regulatory loop to maintain proper Ca(2+) homeostasis in the kidney.
肾脏中离子和溶质经细胞旁途径渗透的生理学机制至关重要，但尚未完全阐明。紧密连接蛋白是细胞旁途径的关键组成部分。紧密连接蛋白功能缺陷可导致多种肾脏疾病，包括低镁血症、高钙尿症和肾结石病。本综述描述了紧密连接蛋白在细胞旁转运机制中发挥生理功能的最新发现，重点介绍了肾脏 Ca(2+) 处理。我们已经揭示了在 Henle 升支粗段（TAL）中细胞旁 Ca(2+) 转运的分子机制，该机制涉及三个重要的紧密连接蛋白基因（claudin-14、-16 和 -19）的功能相互作用，所有这些基因都与人类伴有高钙尿症、肾结石病和骨矿物质损失的肾脏疾病有关。肾脏中的 Ca(2+) 感受器（CaSR）信号一直是个谜。通过分析肾脏中的小非编码 RNA 分子，我们发现了 CaSR 下游的一种新的 microRNA 信号通路，该通路可直接调节紧密连接蛋白-14 基因的表达，并将紧密连接蛋白-14 分子确立为肾脏 Ca(2+) 稳态的关键调节剂。CaSR-microRNAs-紧密连接蛋白的分子级联反应形成了一个调节环，以维持肾脏中适当的 Ca(2+) 稳态。
