State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
J Biol Chem. 2020 Jul 17;295(29):9893-9900. doi: 10.1074/jbc.RA120.013628. Epub 2020 May 27.
Urea transporters are a family of urea-selective channel proteins expressed in multiple tissues that play an important role in the urine-concentrating mechanism of the mammalian kidney. Previous studies have shown that knockout of urea transporter (UT)-B, UT-A1/A3, or all UTs leads to urea-selective diuresis, indicating that urea transporters have important roles in urine concentration. Here, we sought to determine the role of UT-A1 in the urine-concentrating mechanism in a newly developed UT-A1-knockout mouse model. Phenotypically, daily urine output in UT-A1-knockout mice was nearly 3-fold that of WT mice and 82% of all-UT-knockout mice, and the UT-A1-knockout mice had significantly lower urine osmolality than WT mice. After 24-h water restriction, acute urea loading, or high-protein (40%) intake, UT-A1-knockout mice were unable to increase urine-concentrating ability. Compared with all-UT-knockout mice, the UT-A1-knockout mice exhibited similarly elevated daily urine output and decreased urine osmolality, indicating impaired urea-selective urine concentration. Our experimental findings reveal that UT-A1 has a predominant role in urea-dependent urine-concentrating mechanisms, suggesting that UT-A1 represents a promising diuretic target.
尿素转运体是一组在多种组织中表达的尿素选择性通道蛋白，在哺乳动物肾脏的尿液浓缩机制中发挥着重要作用。先前的研究表明，敲除尿素转运体（UT）-B、UT-A1/A3 或所有 UT 会导致尿素选择性利尿，表明尿素转运体在尿液浓缩中具有重要作用。在这里，我们试图在新开发的 UT-A1 敲除小鼠模型中确定 UT-A1 在尿液浓缩机制中的作用。表型上，UT-A1 敲除小鼠的每日尿量几乎是 WT 小鼠的 3 倍，是所有 UT 敲除小鼠的 82%，并且 UT-A1 敲除小鼠的尿液渗透压明显低于 WT 小鼠。在 24 小时水限制、急性尿素负荷或高蛋白（40%）摄入后，UT-A1 敲除小鼠无法增加尿液浓缩能力。与所有 UT 敲除小鼠相比，UT-A1 敲除小鼠表现出相似的每日尿量增加和尿液渗透压降低，表明尿素选择性浓缩受损。我们的实验结果表明，UT-A1 在尿素依赖性尿液浓缩机制中起主要作用，这表明 UT-A1 是一种很有前途的利尿靶点。
