Generation and phenotypic analysis of mice lacking all urea transporters.
Generation and phenotypic analysis of mice lacking all urea transporters.
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缺乏所有尿素转运蛋白的小鼠的产生和表型分析
DOI：
10.1016/j.kint.2016.09.017
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发表时间：
2017-02
影响因子：
19.6
通讯作者：
Yang B
中科院分区：
文献类型：
--
作者：
Jiang T;Li Y;Layton AT;Wang W;Sun Y;Li M;Zhou H;Yang B
尿素转运蛋白(UT)是一类在多种组织中表达的跨膜尿素选择性通道蛋白，在哺乳动物肾脏的尿液浓缩机制中起着重要作用。UT抑制剂已被证实具有利尿活性，可能被开发为新的利尿剂。为了确定是否所有组织中所有UT的功能缺陷都会导致生理异常，我们建立了一个新的小鼠模型，在该模型中，通过删除包含SLC14a1和SLC14a2基因大部分部分的87kb DNA片段来敲除所有UT。Western印迹分析和免疫荧光分析证实，在ALL-UT基因敲除小鼠中没有尿素转运蛋白的表达。ALL-UT基因敲除小鼠的日尿量是野生型小鼠的近3.5倍，尿液渗透压显著低于野生型小鼠。在缺水、急性尿素负荷或高蛋白摄入后，ALL-UT基因敲除小鼠不能增加尿尿素浓度和渗透压。一个模拟UT基因敲除小鼠模型的计算模型确定了每个UT在尿液浓缩机制中的单独贡献。敲除所有UT还可以降低血压，促进男性生殖系统的成熟。这些结果表明，所有UTS的功能缺陷都导致了尿素选择性尿浓缩缺陷，肾外器官的生理异常很少。
Urea transporters (UT) are a family of transmembrane urea-selective channel proteins expressed in multiple tissues and play an important role in the urine concentrating mechanism of the mammalian kidney. UT inhibitors have been identified to have diuretic activity and might be developed as novel diuretics. To determine if functional deficiency of all UTs in all tissues causes physiological abnormality, we established a novel mouse model in which all UTs were knocked out by deleting an 87 kb of DNA fragment containing most parts of Slc14a1 and Slc14a2 genes. Western blot analysis and immunofluorescence confirmed that there is no expression of urea transporter in all-UT-knockout mice. Daily urine output was nearly 3.5-fold higher, with significantly lower urine osmolality, in all-UT-knockout-mice than that in wild-type mice, and urine osmolality was significantly lower. All-UT-knockout mice were not able to increase urinary urea concentration and osmolality after water deprivation, acute urea loading or high protein intake. A computational model that simulated UT knockout mouse models identified the individual contribution of each UT in urine concentrating mechanism. Knocking out all UTs also decreased the blood pressure and promoted the maturation of the male reproductive system. These results revealed that functional deficiency of all UTs caused urea selective urine concentrating defect with little physiological abnormality in extrarenal organs.