title: Urat1-Uox double knockout mice are experimental animal models of renal hypouricemia and exercise-induced acute kidney injury.
abstract: Renal hypouricemia (RHUC) is a hereditary disease characterized by a low level of plasma urate but with normal urinary urate excretion. RHUC type 1 is caused by mutations of the urate transporter URAT1 gene (SLC22A12). However, the plasma urate levels of URAT1 knockout mice are no different from those of wild-type mice. In the present study, a double knockout mouse, in which the URAT1 and uricase (Uox) genes were deleted (Urat1-Uox-DKO), were used as an experimental animal model of RHUC type 1 to investigate RHUC and excise-induced acute kidney injury (EIAKI). Mice were given a variable content of allopurinol for one week followed by HPLC measurement of urate and creatinine concentrations in spot urine and blood from the tail. The urinary excretion of urate in Urat1-Uox-DKO mice was approximately 25 times higher than those of humans. With allopurinol, the plasma urate levels of Urat1-Uox-DKO mice were lower than those of Uox-KO mice. There were no differences in the urinary urate excretions between Urat1-Uox-DKO and Uox-KO mice administered with 9 mg allopurinol /100 g feed. In the absence of allopurinol, plasma creatinine levels of some Urat1-Uox-DKO mice were higher than those of Uox-KO mice. Consequently, hypouricemia and normouricosuria may indicate that the Urat1-Uox-DKO mouse administered with allopurinol may represent a suitable animal model of RHUC type 1. Urat1-Uox-DKO mice without allopurinol exhibited acute kidney injury, thus providing additional benefit as a potential animal model for EIAKI. Finally, our data indicate that allopurinol appears to provide prophylactic effects for EIAKI.
authors.affiliation: a Department of Human Physiology & Pathology , Faculty of Pharma-Sciences, Teikyo University , Tokyo , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hosoyamada
authors.affiliation: b Department of Practical Pharmacology , Faculty and Graduate School of Pharmaceutical Sciences, Chiba University , Chiba , Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tsurumi
authors.affiliation: b Department of Practical Pharmacology , Faculty and Graduate School of Pharmaceutical Sciences, Chiba University , Chiba , Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Hirano
authors.affiliation: a Department of Human Physiology & Pathology , Faculty of Pharma-Sciences, Teikyo University , Tokyo , Japan.
authors.forename: Naoko H
authors.initials: NH
authors.lastname: Tomioka
authors.affiliation: b Department of Practical Pharmacology , Faculty and Graduate School of Pharmaceutical Sciences, Chiba University , Chiba , Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: c Department of Bioscience , National Cardiovascular Center Research Institute , Osaka , Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.affiliation: d Department of Internal Medicine , Faculty of Medicine, Teikyo University , Tokyo , Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Uchida
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D006074:Gout Suppressants / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D015499:Renal Tubular Transport, Inborn Errors / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014503:Urate Oxidase / Q000235:genetics* / Q000378:metabolism; D014527:Uric Acid / Q000652:urine; D014545:Urinary Calculi / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D006074:Gout Suppressants; D027361:Organic Anion Transporters; C109687:Slc22a12 protein, mouse; D014527:Uric Acid; D000493:Allopurinol; D003404:Creatinine; D014503:Urate Oxidase
keywords: Renal hypouricemia; allopurinol; animal models; urate transporter; uricase