title: Generation and phenotypic analysis of mice lacking all urea transporters.
abstract: 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 diuretic activity and could 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 these 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. 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. Thus, functional deficiency of all UTs caused a urea-selective urine-concentrating defect with little physiological abnormality in extrarenal organs.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Mathematics, Duke University, Durham, North Carolina, USA.
authors.forename: Anita T
authors.initials: AT
authors.lastname: Layton
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China. Electronic address: baoxue@bjmu.edu.cn.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001794:Blood Pressure; D003198:Computer Simulation; D004044:Dietary Proteins / Q000378:metabolism; D005260:Female; D005838:Genotype; D007668:Kidney / Q000378:metabolism*; D007671:Kidney Concentrating Ability; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009994:Osmolar Concentration; D010641:Phenotype; D065667:Renal Elimination; D012098:Reproduction; D013997:Time Factors; D014508:Urea / Q000378:metabolism* / Q000652:urine; D014554:Urination; D014566:Urogenital System / Q000254:growth & development / Q000378:metabolism; D014868:Water Deprivation; D000096982:Urea Transporters
chemical_list: D004044:Dietary Proteins; D026901:Membrane Transport Proteins; D014508:Urea; D000096982:Urea Transporters
keywords: animal model; gene targeting; knockout; renal physiology; urine concentration