{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:21:06Z","timestamp":1792905666189,"version":"4.5.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26460347"],"award-info":[{"award-number":["26460347"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2022,2]]},"abstract":"\n Background<\/jats:title>\n \n Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1\/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity\n Urat1<\/jats:italic>\n -\n Uox<\/jats:italic>\n double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n The novel\n Urat1<\/jats:italic>\n -\n Uox<\/jats:italic>\n DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Urat1<\/jats:italic>\n -\n Uox<\/jats:italic>\n DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition,\n Urat1<\/jats:italic>\n -\n Uox<\/jats:italic>\n DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na\n +<\/jats:sup>\n -K\n +<\/jats:sup>\n -ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Urat1<\/jats:italic>\n -\n Uox<\/jats:italic>\n DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1\n \u03b2 via<\/jats:italic>\n NLRP3 inflammasome signaling and Na\n +<\/jats:sup>\n -K\n +<\/jats:sup>\n -ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2021050616","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T12:55:20Z","timestamp":1637326520000},"page":"326-341","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice"],"prefix":"10.1681","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9393-6099","authenticated-orcid":false,"given":"Takuji","family":"Hosoya","sequence":"first","affiliation":[{"name":"Department of Human Physiology and Pathology, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan"},{"name":"Biological Research Department, Research Institute, Fuji Yakuhin Co., Ltd., Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunya","family":"Uchida","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6868-0626","authenticated-orcid":false,"given":"Shigeru","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko H.","family":"Tomioka","sequence":"additional","affiliation":[{"name":"Department of Human Physiology and Pathology, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Biological Research Department, Research Institute, Fuji Yakuhin Co., Ltd., Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Hosoyamada","sequence":"additional","affiliation":[{"name":"Department of Human Physiology and Pathology, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,2]]},"reference":[{"key":"B2-20250823","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nature742","article-title":"Molecular identification of a renal urate anion exchanger that regulates blood urate levels","volume":"417","author":"Enomoto","year":"2002","journal-title":"Nature"},{"key":"B3-20250823","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/01.ASN.0000105320.04395.D0","article-title":"Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate 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