hURAT1 Transgenic Mouse Model for Evaluating Targeted Urate-Lowering Agents

IF 2.4 4区 医学 Q2 RHEUMATOLOGY International Journal of Rheumatic Diseases Pub Date : 2024-12-30 DOI:10.1111/1756-185X.70034
Weiyan Cai, Miyi Yang, Qinghe Zhao, Guohua Yi, Peihui Lin, Apeng Chen, Gejing De
{"title":"hURAT1 Transgenic Mouse Model for Evaluating Targeted Urate-Lowering Agents","authors":"Weiyan Cai,&nbsp;Miyi Yang,&nbsp;Qinghe Zhao,&nbsp;Guohua Yi,&nbsp;Peihui Lin,&nbsp;Apeng Chen,&nbsp;Gejing De","doi":"10.1111/1756-185X.70034","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Urate transporter 1 (URAT1) is a well-known therapeutic target for reducing urate levels in the treatment of hyperuricemia and gout. However, current pharmacological studies have failed to evaluate the efficacy of URAT1 inhibitors in non-primate animal models. We established a <i>human URAT1</i> (<i>hURAT1</i>) transgenic knock-in (KI) mouse model to assess uricosuric agents' effectiveness and characterize URAT1-caused pathogenesis.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We generated <i>hURAT1</i> transgenic mice using CRISPR/Cas9 KI technique. <i>mUrat1</i> knockout was achieved by replacing exon 1 coding sequence with a human <i>SLC22A12</i> coding sequence (CDS)-pA cassette. Based on the above transgenic mice, a hyperuricemia model was further established by hypoxanthine administration.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The <i>hURAT1</i>-KI mice successfully expressed hURAT1 protein to the apical side of the kidney proximal tubule epithelium, where native human URAT1 is localized in human kidney. Upon hypoxanthine challenge, the blood uric acid (UA) level was elevated in <i>hURAT1-</i>KI mice (251 μmol/L), showing an approximately 37% increase compared to wild-type (WT) mice (183.5 μmol/L). The elevated blood UA level could be alleviated by hURAT1 inhibitor benzbromarone treatment in the <i>hURAT1</i>-KI mice (164.2 μmol/L vs. 251 μmol/L, <i>p</i> &lt; 0.05) whereas no response was observed in <i>WT</i> littermates (168.8 μmol/L vs. 183.5 μmol/L).</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>The <i>hURAT1</i>-KI hyperuricemia mouse model would be valuable for preclinical evaluation of gout treatment with urate-lowering drugs and for studying UA metabolic complexities in humans.</p>\n </section>\n </div>","PeriodicalId":14330,"journal":{"name":"International Journal of Rheumatic Diseases","volume":"28 1","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.70034","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background

Urate transporter 1 (URAT1) is a well-known therapeutic target for reducing urate levels in the treatment of hyperuricemia and gout. However, current pharmacological studies have failed to evaluate the efficacy of URAT1 inhibitors in non-primate animal models. We established a human URAT1 (hURAT1) transgenic knock-in (KI) mouse model to assess uricosuric agents' effectiveness and characterize URAT1-caused pathogenesis.

Methods

We generated hURAT1 transgenic mice using CRISPR/Cas9 KI technique. mUrat1 knockout was achieved by replacing exon 1 coding sequence with a human SLC22A12 coding sequence (CDS)-pA cassette. Based on the above transgenic mice, a hyperuricemia model was further established by hypoxanthine administration.

Results

The hURAT1-KI mice successfully expressed hURAT1 protein to the apical side of the kidney proximal tubule epithelium, where native human URAT1 is localized in human kidney. Upon hypoxanthine challenge, the blood uric acid (UA) level was elevated in hURAT1-KI mice (251 μmol/L), showing an approximately 37% increase compared to wild-type (WT) mice (183.5 μmol/L). The elevated blood UA level could be alleviated by hURAT1 inhibitor benzbromarone treatment in the hURAT1-KI mice (164.2 μmol/L vs. 251 μmol/L, p < 0.05) whereas no response was observed in WT littermates (168.8 μmol/L vs. 183.5 μmol/L).

Conclusion

The hURAT1-KI hyperuricemia mouse model would be valuable for preclinical evaluation of gout treatment with urate-lowering drugs and for studying UA metabolic complexities in humans.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
用于评估靶向降尿酸药物的 hURAT1 转基因小鼠模型
背景:在高尿酸血症和痛风的治疗中,尿酸转运蛋白1 (URAT1)是一个众所周知的降低尿酸水平的治疗靶点。然而,目前的药理学研究未能评估URAT1抑制剂在非灵长类动物模型中的功效。我们建立了人类URAT1 (hURAT1)转基因敲入(KI)小鼠模型,以评估尿尿药物的有效性并表征URAT1引起的发病机制。方法:采用CRISPR/Cas9 KI技术制备hURAT1转基因小鼠。mUrat1基因敲除是通过用人类SLC22A12编码序列(CDS)-pA卡带替换外显子1编码序列实现的。在上述转基因小鼠的基础上,进一步应用次黄嘌呤建立高尿酸血症模型。结果:hURAT1- ki小鼠成功地将hURAT1蛋白表达到肾近端小管上皮的顶侧,这是人类肾脏中天然URAT1的位置。在次黄嘌呤刺激下,hURAT1-KI小鼠血尿酸(UA)水平升高(251 μmol/L),比野生型(WT)小鼠(183.5 μmol/L)增加约37%。hURAT1抑制剂苯溴马隆治疗hURAT1- ki小鼠血尿酸水平升高(164.2 μmol/L vs 251 μmol/L), p。结论:hURAT1- ki高尿酸血症小鼠模型可用于临床前评估降尿酸药物治疗痛风的疗效和研究人类尿酸代谢复杂性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
相关文献
International arbitration : law and practice
IF 4.3 2区 社会学American Journal of International LawPub Date : 1960-04-01 DOI: 10.2307/2195272
K. S. Carlston
来源期刊
CiteScore
3.70
自引率
4.00%
发文量
362
审稿时长
1 months
期刊介绍: The International Journal of Rheumatic Diseases (formerly APLAR Journal of Rheumatology) is the official journal of the Asia Pacific League of Associations for Rheumatology. The Journal accepts original articles on clinical or experimental research pertinent to the rheumatic diseases, work on connective tissue diseases and other immune and allergic disorders. The acceptance criteria for all papers are the quality and originality of the research and its significance to our readership. Except where otherwise stated, manuscripts are peer reviewed by two anonymous reviewers and the Editor.
期刊最新文献
Issue Information Nailfold Capillaroscopy as Predictor for Autoantibody Test Results The Evaluation of PNPLA2, ATGL, and G0S2 Levels in Serum and PBMCs of the Newly Diagnosed and the Chronic Patients With Rheumatoid Arthritis Balancing Effective Treatments With Potential Threats: The Impact of Biologic Agent Use on Tuberculosis Development in Children With Chronic Inflammatory Disorders Case Report: Effective Treatment of Pyoderma Gangrenosum in a Patient Complicated With Diabetic Foot Ulcer Using Intravenous Immunoglobulin and Adalimumab
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1