Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load.
Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load.
复制标题
尿鸟苷蛋白敲除小鼠血压升高，对肠内氯化钠负荷的利尿钠反应受损。
DOI：
10.1172/jci18743
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Cohen,MitchellB
中科院分区：
文献类型：
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作者：
Lorenz,JohnN;Nieman,Michelle;Sabo,Jenine;Sanford,LPhilip;Hawkins,JenniferA;Elitsur,Noeet;Gawenis,LaraR;Clarke,LaneL;Cohen,MitchellB
鸟苷素和尿鸟苷素是在肠和肾中合成的肽，已被假定具有旁分泌和内分泌功能，形成潜在的肠-肾连接以协调盐摄入与尿钠排泄。为了探索尿鸟苷素在体内钠排泄调节中的作用，我们建立了基因靶向小鼠，其中尿鸟苷素基因表达已被消融。北方和西方的分析证实，在敲除小鼠的尿鸟苷肽信息和蛋白质的情况下，和cGMP水平降低的小肠粘膜。空肠的Ussing室分析显示，Na+/H+交换介导的Na+吸收和组织电导在敲除动物中没有改变，但短路电流，产电阴离子分泌的指数，减少。肾清除率测量结果表明，尿鸟苷素缺乏导致肠内负荷的NaCl排泄能力受损，主要是由于肾脏Na+重吸收的不适当增加。最后，血压的遥测记录表明，在尿鸟苷素基因敲除动物的平均动脉压增加，这是独立的饮食中的盐摄入量的水平。总之，这些研究结果建立了一个作用，尿鸟苷素在肠-肾通信轴，以及该轴的基本原则，在体内盐稳态的维持。
Guanylin and uroguanylin, peptides synthesized in the intestine and kidney, have been postulated to have both paracrine and endocrine functions, forming a potential enteric-renal link to coordinate salt ingestion with natriuresis. To explore the in vivo role of uroguanylin in the regulation of sodium excretion, we created gene-targeted mice in which uroguanylin gene expression had been ablated. Northern and Western analysis confirmed the absence of uroguanylin message and protein in knockout mice, and cGMP levels were decreased in the mucosa of the small intestine. Ussing chamber analysis of jejunum revealed that Na+/H+ exchanger–mediated Na+absorption and tissue conductance was not altered in the knockout animals, but short-circuit current, an index of electrogenic anion secretion, was reduced. Renal clearance measurements showed that uroguanylin deficiency results in impaired ability to excrete an enteral load of NaCl, primarily due to an inappropriate increase in renal Na+reabsorption. Finally, telemetric recordings of blood pressure demonstrated increased mean arterial pressure in uroguanylin knockout animals that was independent of the level of dietary salt intake. Together, these findings establish a role for uroguanylin in an enteric-renal communication axis as well as a fundamental principle of this axis in the maintenance of salt homeostasis in vivo.