Urat1-Uox double knockout mice are experimental animal models of renal hypouricemia and exercise-induced acute kidney injury
Urat1-Uox double knockout mice are experimental animal models of renal hypouricemia and exercise-induced acute kidney injury
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DOI：
10.1080/15257770.2016.1143559
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发表时间：
2016-01-01
影响因子：
1.3
通讯作者：
Uchida, Shunya
中科院分区：
文献类型：
--
作者：
Hosoyamada, Makoto;Tsurumi, Yu;Uchida, Shunya
肾性低尿酸血症（RHUC）是一种遗传性疾病，其特征是血浆尿酸水平低，但尿尿酸排泄正常。RHUC 1型是由尿酸盐转运蛋白URAT 1基因（SLC 22 A12）突变引起的。然而，URAT 1基因敲除小鼠的血浆尿酸水平与野生型小鼠没有差异。在本研究中，使用URAT 1和尿酸酶（Uox）基因缺失的双敲除小鼠（Urat 1-Uox-DKO）作为RHUC 1型的实验动物模型，以研究RHUC和切除诱导的急性肾损伤（EIAKI）。小鼠给予可变含量的别嘌呤醇一周，然后用HPLC测量点尿和尾部血液中的尿酸盐和肌酐浓度。Urat 1-Uox-DKO小鼠的尿酸盐尿排泄量约为人类的25倍。使用别嘌呤醇时，Urat 1-Uox-DKO小鼠的血浆尿酸盐水平低于Uox-KO小鼠。给予9 mg别嘌呤醇/100 g饲料的Urat 1-Uox-DKO和Uox-KO小鼠之间的尿液尿酸盐排泄量没有差异。在不存在别嘌呤醇的情况下，一些Urat 1-Uox-DKO小鼠的血浆肌酐水平高于Uox-KO小鼠。因此，低尿酸血症和正常尿酸尿可能表明给予别嘌呤醇的Urat 1-Uox-DKO小鼠可能代表1型RHUC的合适动物模型。不含别嘌呤醇的Urat 1-Uox-DKO小鼠表现出急性肾损伤，因此作为EIAKI的潜在动物模型提供了额外的益处。最后，我们的数据表明，别嘌呤醇似乎提供了预防作用的EIAKI。
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.