肾结石(calculus of kidney)指发生于肾盏、肾盂及肾盂与输尿管连接部的结石。多数位于肾盂肾盏内,肾实质结石少见。肾是泌尿系形成结石的主要部位,其他任何部位的结石都可以原发于肾脏,输尿管结石几乎均来自肾脏,而且肾结石比其他任何部位结石更易直接损伤肾脏,因此早期诊断和治疗非常重要。每年估计有100多万美国人被确诊患有肾结石。
现在,圣路易斯华盛顿大学医学院科学家的一项新研究提供的证据解释了为什么有些人容易患肾结石。他们的发现为找到有效的药物治疗和评估肾结石风险测试铺平了道路。
Jianghui Hou博士、医学助理教授说:现在,我们终于有了一个更完整的图片能详细介绍为什么有些人容易患肾结石。研究论文发表在EMBO Journal上。
由于小鼠的肾脏功能与人类似,新的发现可以帮助科学家了解患者肾结石的根源。
但是肾结石部分原因是由基因引起的。一种常见的遗传变异基因就是claudin-14,最近研究发现claudin-14会导致肾结石风险大幅增加,这一数值大约为65%。在新研究中,研究人员揭示了基因活性的改变是如何影响结石的发展。
通常情况下,claudin-14基因在肾脏中是不表达的。这项新的研究表明其表达被RNA两个片段沉默基因所抑制。
当 claudin-14被抑制时,肾脏的过滤系统工作运行正常。但是,当人们吃的饮食中钙或高盐,同时并没有喝足够水的话,小分子RNA释放对 claudin 14的抑制。基因活性的增加,阻断了钙从血液中回收。Hou和他的团队发现claudin-14阻断钙进入细胞紧密连接通道。
claudin-14的变异的人失去了调节基因活性的能力,肾结石的风险增加。研究人员表示可能有一天有可能开发出诊断测试测量尿中排出claudin-14的蛋白水平的技术方法。
Claudin-14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway
Yongfeng Gong, Vijayaram Renigunta, Nina Himmerkus, Jiaqi Zhang, Aparna Renigunta, Markus Bleich and Jianghui Hou
The paracellular claudin channel of the thick ascending limb (TAL) of Henle is critical for Ca++ reabsorption in the kidney. Genome-wide association studies (GWASs) have identified claudin-14 associated with hypercalciuric nephrolithiasis. Here, we show that claudin-14 promoter activity and tran- are exclusively localized in the TAL. Under normal dietary condition, claudin-14 proteins are suppressed by two microRNA molecules (miR-9 and miR-374). Both microRNAs directly target the 3′-UTR of claudin-14 mRNA; induce its mRNA decay and translational repression in a synergistic manner. Through physical interaction, claudin-14 blocks the paracellular cation channel made of claudin-16 and -19, critical for Ca++ reabsorption in the TAL. The tran- and protein levels of claudin-14 are upregulated by high Ca++ diet, while downregulated by low Ca++ diet. Claudin-14 knockout animals develop hypermagnesaemia, hypomagnesiuria, and hypocalciuria under high Ca++ dietary condition. MiR-9 and miR-374 tran- levels are regulated by extracellular Ca++ in a reciprocal manner as claudin-14. The Ca++ sensing receptor (CaSR) acts upstream of the microRNA-claudin-14 axis. Together, these data have established a key regulatory role for claudin-14 in renal Ca++ homeostasis.