The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism

• Authors: Xiaoqiang Geng, Peking University; Shun Zhang, Peking University; Jinzhao He, Peking University; Ang Ma, Peking University; Yingjie Li, Peking University; Min Li, Peking University; Hong Zhou, Peking University; Guangping Chen, Emory University; Baoxue Yang, Peking University
• Journal Title: JOURNAL OF BIOLOGICAL CHEMISTRY
• Volume: Volume 295, Number 29
• Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | 2020-07-17, Pages 9893-9900
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1074/jbc.RA120.013628
• Subjects: Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; animal model; CRISPR; Cas9; gene knockout; kidney; renal physiology; UT-A1; urea transporter; diuresis; electrolyte metabolism; UT-A; MICE LACKING; MEMBRANE ACCUMULATION; WATER CHANNEL; MESSENGER-RNA; CLONING; LOCALIZATION; KNOCKOUT; GENE; PHOSPHORYLATION

Abstract

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 UTA1–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 UTA1 represents a promising diuretic target.