Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 29, Pages 9893-9900Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.013628
Keywords
animal model; CRISPR; Cas9; gene knockout; kidney; renal physiology; UT-A1; urea transporter; diuresis; electrolyte metabolism
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Funding
- National Natural Science Foundation of China [81620108029, 81974083, 81330074, 81800388]
- Beijing Natural Science Foundation [7172113]
- China Postdoctoral Science Foundation [2018M630049]
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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.
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