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

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 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. 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. Urea is the main end product of protein metabolism in mammals and plays a critical role in the urine-concentrating and water-conservation mechanism (1Fenton R.A. Chou C.L. Sowersby H. Smith C.P. 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Blount M.A. Sands J.M. of urea transporter urinary in the of urea transporter Am. 2016; PubMed Scopus Google mice UT-A1 that expression of UT-A1 in mice was to urine-concentrating indicating the role of UT-A1 in the urea of inner medulla and in the urine-concentrating UT-A1 is expressed in the plasma membrane and is expressed in the basolateral plasma membrane of the principle cells at the end of M.A. Klein J.D. Martin C.F. Tchapyjnikov D. Sands J.M. Forskolin stimulates phosphorylation and membrane accumulation of UT-A3.Am. J. Physiol. Renal Physiol. 2007; 293 (17686955): F1308-F131310.1152/ajprenal.00197.2007Crossref PubMed Scopus (61) Google Scholar, S. Knepper M.A. H.W. Cellular and subcellular of vasopressin-regulated water channel in rat kidney.Proc. Natl. Acad. Sci. U.S.A. 1993; PubMed Scopus Google Scholar), is to determine the of UT-A1 and to urea-dependent urine-concentrating mice are a to determine the role of UT-A1 in urea and the urine-concentrating both UT-A1 and the as as the of the first in gene is to UT-A1 there is a at the of that is in the of UT-A1 R.A. Cottingham C.A. Stewart G.S. Howorth A. Hewitt J.A. Smith C.P. Structure and characterization of the mouse UT-A gene (Slc14a2).Am. J. Physiol. Renal Physiol. 2002; 282 (11880324): F630-F63810.1152/ajprenal.00264.2001Crossref PubMed Scopus (70) Google Scholar, S.M. T. A. Sands J.M. Cloning and characterization of the human urea transporter UT-A1 and of the human Slc14a2 J. Physiol. Renal Physiol. 2001; PubMed Google Scholar, Y. M. A. T. Sands J.M. Bagnasco S.M. Cloning of the rat Slc14a2 gene and of the UT-A urea 2001; PubMed Scopus Google Scholar). we an of the of UT-A1 mRNA to the gene on the expression of we an mouse model. The phenotypic analysis that UT-A1 to a urea-selective urine-concentrating defect and 3-fold daily urine output with WT and 82% of mice. mice exhibited kidney and phenotype analysis that UT-A1 deletion blood and had on and The experimental that UT-A1, plays a predominant role in urea-dependent urine concentration. UT-A1 is an diuretic and the UT-A1 developed as mice were by on the of UT-A gene Slc14a2 R.A. Cottingham C.A. Stewart G.S. Howorth A. Hewitt J.A. Smith C.P. Structure and characterization of the mouse UT-A gene (Slc14a2).Am. J. Physiol. Renal Physiol. 2002; 282 (11880324): F630-F63810.1152/ajprenal.00264.2001Crossref PubMed Scopus (70) Google as and shown in analysis that UT-A1 and were expressed in the renal inner and UT-A2 was expressed in the renal medulla in WT mice. UT-A1 was in the UT-A2 and were in mice B and that UT-A1 was expressed in basolateral of and UT-A2 expressed in medulla were that UT-A1 was analysis of from of mice a nearly to the distribution and analysis of by mouse WT and mice was different mice, mice, and WT mice urine output was shown in The mice exhibited the urine with WT mice, which was of the mice and The urine osmolality of mice was lower than that of WT mice and was to mice and was in to 24-h water osmolality in the WT mice only in the mice, in with the mice was in the of the of the two that there was of collecting in the in mice on of The of the of the was shown in to mice, the urea in mice was significantly lower than that in WT mice. was in and mice, mice, and WT mice of the role of UT-A1 in the urine mechanism in we the of and that the of mice was to that of WT mice suggesting that UT-A1 deletion and and urea were in urine and plasma Urinary urea was significantly in mice, in with mice. plasma urea was in and WT mice. was in plasma and the metabolism was in the of UT-A1 the of UT-A1 in the to urea the mice were to an acute urea of daily urea as T. Y. Wang W. Y. M. Zhou H. Yang B. and phenotypic analysis of mice all urea 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). the first of urea WT mice significantly their urea and urinary osmolality with a in urinary mice in urinary osmolality and urinary urea with urine The of urea was in both mice and WT mice After urea to the urinary osmolality and urea in WT mice in mice, urinary osmolality was only and urine output indicating that mice urea in the medulla an acute urea of urea significantly the of the kidney to urinary in WT mice, was in mice of the urine output in the the of was in both WT and mice to the urea The of was in two the by which mice of different their renal to different of urea WT and mice were for 1 with a or protein or as the only of respectively. had a on urine which in the two with the of different protein the urine was in mice than in WT mice Urinary osmolality and urea were with the of protein in WT mice in mice B and suggesting that the accumulation of urea in the was to a protein the and urea were in the two and elevated along with the protein intake, and there was two with the protein the lower blood in and mice with WT mice T. Y. Wang W. Y. M. Zhou H. Yang B. and phenotypic analysis of mice all urea 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Y. Y. Wang W. J. F. Y. Zhou H. Yang B. of urea transporter UT-B and blood via 2016; PubMed Scopus Google Scholar), we blood of WT and mice a with a Y. Y. Y. Wang W. J. F. Y. Zhou H. Yang B. of urea transporter UT-B and blood via 2016; PubMed Scopus Google Scholar). The that blood in in blood in in and in in were all in both indicating that deletion or blood the UT-A1 and are expressed in the inner collecting duct plasma membrane and basolateral plasma M.A. Klein J.D. Martin C.F. Tchapyjnikov D. Sands J.M. Forskolin stimulates phosphorylation and membrane accumulation of UT-A3.Am. J. Physiol. Renal Physiol. 2007; 293 (17686955): F1308-F131310.1152/ajprenal.00197.2007Crossref PubMed Scopus (61) Google Scholar, S. Knepper M.A. H.W. Cellular and subcellular of vasopressin-regulated water channel in rat kidney.Proc. Natl. Acad. Sci. U.S.A. 1993; PubMed Scopus Google Scholar). of in urine and urea-selective diuresis, indicating the role of UT-A1 and in the urine-concentrating that UT-A1 the urine-concentrating defect in mice J.D. Wang Y. A. R.T. Blount M.A. Sands J.M. of urea transporter urinary in the of urea transporter Am. 2016; PubMed Scopus Google Scholar). studies the predominant role of UT-A1 in urine The mouse is a to the of UT-A1 in urea-dependent urine-concentrating the mouse is a the gene of Slc14a2 the UT-A1 to proteins was to the mice by the UT-A1 gene six UT-A on a of for the and UT-A1 splicing we an by a of of UT-A1 to the splicing the of the UT-A1 mRNA and the UT-A1 protein the protein expression of by The mouse with UT-A1 deletion was and by of functional that mice exhibited a urine output and urine-concentrating ability. The inner medullary urea in mice was significantly lower than that in WT mice, and was in or in blood the two the from and mice, is that UT-A1 the urea of UT-A3, or UTs in kidney the impaired urine-concentrating suggesting UT-A1 as an diuretic target. the and mice, UT-A1 deletion had in blood was in plasma or in mice, that UT-A1 deletion plasma and were and WT mice, indicating that deletion of UT-A1 urine output in the and medulla of mice, for the collecting duct by urine to mice. mice urine output than WT mice and lower urine output than mice. The is that urea was at the end of and the of UT-B and to inner urea concentration. Compared with WT mice, an acute a urea urinary urea and osmolality, indicating that mice urea in the were to mice, suggesting the predominant role of UT-A1 in urea and in kidney. the of the there are models of UT mice, B. A. Verkman A.S. concentrating defect in mice urea transporter Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), (25Fenton R.A. Chou C.L. Stewart G.S. Smith C.P. Knepper M.A. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15123796): 7469-747410.1073/pnas.0401704101Crossref PubMed Scopus (203) Google Scholar), S. T. M. M. S. urea accumulation in the inner medulla of mice the urea transporter Cell. Biol. 2005; PubMed Scopus Google Scholar), T. Zhou Zhou H. X. Yang B. of thin descending limb urea transport in renal urea and the urine concentrating J. Physiol. Renal Physiol. PubMed Scopus Google Scholar), with UT-A1 J.D. Wang Y. A. R.T. Blount M.A. Sands J.M. of urea transporter urinary in the of urea transporter Am. 2016; PubMed Scopus Google Scholar), T. Y. Wang W. Y. M. Zhou H. Yang B. and phenotypic analysis of mice all urea 2017; Full Text Full Text PDF PubMed Scopus Google Scholar), and mice were at The of urine-concentrating in mice was by urine urine osmolality, and urine urea The urine output was shown as mice mice mice mice mice mice mice with UT-A1 mice WT mice. The urine osmolality was shown as mice mice mice mice mice mice mice WT mice. The urine urea was shown as mice mice mice mice mice mice WT mice. The urine output of mice is than that of mice, which is to the of UT-B and that UT-A1 is the important UT in urea and urea-selective urine concentrating of urea in the kidney of WT and mice. Urea are by for that UT-A1 deletion or the and Previous findings that UT developed as and metabolism T. Y. Wang W. Y. M. Zhou H. Yang B. and phenotypic analysis of mice all urea 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, B. Urea and urine concentrating from studies in mice.Am. J. Physiol. Renal Physiol. 2005; 288 PubMed Scopus Google Scholar, X. 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Zhou Han J. Yang B. urea transporter UT-B PubMed Scopus Google and to and in J. Zhou H. J. Lei T. Wang W. Y. G. Yang B. Urea transporter UT-B deletion and in mouse PubMed Scopus Google Scholar), which to elevated of to elevated blood urea and as and cell in to the knockout of UT-A1 the blood urea or physiological for the The the to developed diuretic with the with The mouse we is an in which to the of UT-A1 on the of UT-A gene Slc14a2 and we a of of UT-A1 to the splicing and the of the UT-A1 mRNA and the UT-A1 protein were by by analysis T. Y. Wang W. Y. M. Zhou H. Yang B. and phenotypic analysis of mice all urea 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). mice the of that Slc14a2 gene in the were to mice. mice were as T. Y. Wang W. Y. M. Zhou H. Yang B. and phenotypic analysis of mice all urea 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). The were by the on Renal tissues and inner were in protein a protein was The were on and to After the were with UT-A1, or by G. Fröhlich O. Yang Y. Klein J.D. Sands J.M. of urea transporter UT-A1 to Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, G. G. Fröhlich O. Klein J.D. Sands J.M. UT-A1 urea transporter J. PubMed Scopus Google and or was and the were developed with an and with a was by and the of the The kidney tissues were and in The were to a in was at on a The were with and at to the were with UT-A1, or The Jackson were for and in a for 1 to the The were by tissues were and in for tissues were at for and The were by WT and mice were in for mice After of to the urine were for urine were from the mice to and and 24-h of and 24-h urine output and water were with were in by of the was from blood cells by osmolality was by and plasma were by the the mice were with and a from two a and a and was via the A. Y. S. J. D. S. S. F. J. J. F. N. D. of renal in mice.Am. J. Physiol. Renal Physiol. PubMed Scopus Google Scholar). the of was and in a the of the was for After of the the were The was from the in plasma of a the of the and an A. Y. S. J. D. S. S. F. J. J. F. N. D. of renal in mice.Am. J. Physiol. Renal Physiol. PubMed Scopus Google Scholar). WT and mice were for the urea to was to of 1 urea was in for and the urea and as was by urea from WT and mice were with or protein or as the only of After on 24-h urine was and as was a with a was daily at and were are expressed as the S.D. was at The of all from were A analysis of by or a with by was to the the were in are the with urea transporter inner medulla inner medullary collecting duct analysis of

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