{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T02:10:21Z","timestamp":1792807821511,"version":"4.5.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Dotinurad treatment slows the progression of kidney disease in a mouse model of Alport syndrome, a genetic model of CKD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Dotinurad may represent a potential therapeutic strategy for CKD management.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hyperuricemia contributes to inflammatory conditions such as gout and is associated with liver dysfunction, cardiovascular disease, and immune cell activation. While the benefits of uric acid (UA)\u2013lowering therapy in patients with CKD remain uncertain, dotinurad (DD), a selective urate transporter 1 (URAT1) inhibitor, may provide renal benefits by reducing excessive UA reabsorption. This study investigates the effects of DD on kidney function in a mouse model of Alport syndrome, a genetic model of CKD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A mouse model of Alport syndrome was used to evaluate the effects of DD on kidney function. Mice were treated with DD, and their lifespan, urinary albumin-to-creatinine ratios, serum creatinine levels, urinary uric acid-to-creatinine ratios, and serum UA levels were assessed. Histologic analysis was performed to evaluate glomerulosclerosis and tubulointerstitial fibrosis. In addition, RNA sequencing was conducted to identify gene expression changes, with real-time RT-PCR used to validate key findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>DD-treated mice exhibited a significantly longer lifespan than control mice. They also showed lower urinary albumin-to-creatinine ratios and serum creatinine levels, while urinary uric acid-to-creatinine ratios and serum UA levels remained unchanged. Histologic analysis demonstrated reduced glomerulosclerosis and tubulointerstitial fibrosis in DD-treated mice. RNA sequencing revealed a downregulation of inflammatory cytokines, which was further validated by RT-PCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that DD may exert renoprotective effects in CKD. Further research is needed to confirm these effects in clinical settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.34067\/kid.0000000910","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T16:00:46Z","timestamp":1754668846000},"page":"1671-1681","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Dotinurad, a Novel Urate Reabsorption Inhibitor, Prolongs Survival in Alport Mice"],"prefix":"10.34067","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4132-6648","authenticated-orcid":false,"given":"Ryosuke","family":"Saiki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6663-133X","authenticated-orcid":false,"given":"Kan","family":"Katayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsuki","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9460-3847","authenticated-orcid":false,"given":"Lupiya","family":"Kimena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Oda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8881-9574","authenticated-orcid":false,"given":"Yasuo","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Murata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8067-398X","authenticated-orcid":false,"given":"Ryuji","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-6326","authenticated-orcid":false,"given":"Kaoru","family":"Dohi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"issue":"7","key":"B1-20251101","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41584-019-0222-x","article-title":"Mouse models for human hyperuricaemia: a critical review","volume":"15","author":"Lu","year":"2019","journal-title":"Nat Rev Rheumatol."},{"key":"B2-20251101","doi-asserted-by":"crossref","first-page":"1282890","DOI":"10.3389\/fimmu.2023.1282890","article-title":"The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications","volume":"14","author":"Li","year":"2023","journal-title":"Front Immunol."},{"issue":"1","key":"B3-20251101","doi-asserted-by":"crossref","first-page":"20114","DOI":"10.1038\/s41598-021-99623-z","article-title":"Assessment of the relationship between serum uric acid levels and liver enzymes activity in Bangladeshi adults","volume":"11","author":"Molla","year":"2021","journal-title":"Sci Rep."},{"issue":"4","key":"B4-20251101","first-page":"264","article-title":"Higher levels of serum uric acid influences hepatic damage in patients with non-alcoholic fatty liver disease (NAFLD)","volume":"111","author":"Fern\u00e1ndez Rodr\u00edguez","year":"2019","journal-title":"Rev Esp Enferm Dig."},{"issue":"2","key":"B5-20251101","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1053\/j.ajkd.2010.01.024","article-title":"Is high serum uric acid a risk marker or a target for treatment? Examination of its independent effect in a large cohort with low cardiovascular risk","volume":"56","author":"Wen","year":"2010","journal-title":"Am J Kidney Dis."},{"issue":"11","key":"B6-20251101","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1681\/ASN.2014070660","article-title":"Uric acid and cardiovascular events: A Mendelian Randomization Study","volume":"26","author":"Kleber","year":"2015","journal-title":"J Am Soc Nephrol."},{"issue":"1","key":"B7-20251101","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s12872-019-1215-z","article-title":"Serum uric acid and risk of cardiovascular mortality: a systematic review and dose-response meta-analysis of cohort studies of over a million participants","volume":"19","author":"Rahimi-Sakak","year":"2019","journal-title":"BMC Cardiovasc Disord."},{"issue":"10","key":"B8-20251101","first-page":"CD009460","article-title":"Uric acid lowering therapies for preventing or delaying the progression of chronic kidney disease","volume":"10","author":"Sampson","year":"2017","journal-title":"Cochrane Database Syst Rev."},{"issue":"9","key":"B9-20251101","doi-asserted-by":"crossref","first-page":"e1332","DOI":"10.34067\/KID.0000000000000221","article-title":"Management of patients with gout and kidney disease: a review of available therapies and common missteps","volume":"4","author":"Kannuthurai","year":"2023","journal-title":"Kidney360."},{"issue":"6","key":"B10-20251101","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/art.41247","article-title":"2020 American College of Rheumatology guideline for the management of gout","volume":"72","author":"FitzGerald","year":"2020","journal-title":"Arthritis Rheumatol."},{"issue":"2","key":"B11-20251101","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1046\/j.1523-1755.2003.00779.x","article-title":"Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome","volume":"63","author":"Gross","year":"2003","journal-title":"Kidney Int."},{"issue":"7","key":"B12-20251101","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1093\/ndt\/gfh219","article-title":"Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis","volume":"19","author":"Gross","year":"2004","journal-title":"Nephrol Dial Transplant."},{"issue":"3","key":"B13-20251101","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/ajh.2010.231","article-title":"Renal protective effects of aliskiren beyond its antihypertensive property in a mouse model of progressive fibrosis","volume":"24","author":"Gross","year":"2011","journal-title":"Am J Hypertens."},{"issue":"4","key":"B14-20251101","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1681\/ASN.2004100871","article-title":"Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease","volume":"16","author":"Ninichuk","year":"2005","journal-title":"J Am Soc Nephrol."},{"issue":"9","key":"B15-20251101","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1681\/ASN.0000000000000186","article-title":"Finerenone added to RAS\/SGLT2 blockade for CKD in Alport syndrome. Results of a randomized controlled trial with Col4a3-\/- mice","volume":"34","author":"Zhu","year":"2023","journal-title":"J Am Soc Nephrol."},{"issue":"suppl 1","key":"B16-20251101","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10157-019-01816-4","article-title":"Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment","volume":"24","author":"Kumagai","year":"2020","journal-title":"Clin Exp Nephrol."},{"issue":"1","key":"B17-20251101","doi-asserted-by":"crossref","first-page":"20556","DOI":"10.1038\/s41598-021-00159-z","article-title":"Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis","volume":"11","author":"Tanoue","year":"2021","journal-title":"Sci Rep."},{"issue":"9","key":"B18-20251101","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1681\/ASN.2007070829","article-title":"Irradiation prolongs survival of Alport mice","volume":"19","author":"Katayama","year":"2008","journal-title":"J Am Soc Nephrol."},{"issue":"5","key":"B19-20251101","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1681\/ASN.2012070700","article-title":"Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis","volume":"24","author":"Bechtel","year":"2013","journal-title":"J Am Soc Nephrol."},{"issue":"3","key":"B20-20251101","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s10157-023-02419-w","article-title":"Efficacy of dotinurad in patients with severe renal dysfunction","volume":"28","author":"Kurihara","year":"2024","journal-title":"Clin Exp Nephrol."},{"issue":"1","key":"B21-20251101","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12882-024-03535-9","article-title":"Dotinurad restores exacerbated kidney dysfunction in hyperuricemic patients with chronic kidney disease","volume":"25","author":"Amano","year":"2024","journal-title":"BMC Nephrol."},{"key":"B22-20251101","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.2147\/DDDT.S416025","article-title":"The efficacy and safety of dotinurad on uric acid and renal function in patients with hyperuricemia and advanced chronic kidney disease: a single center, retrospective analysis","volume":"17","author":"Yanai","year":"2023","journal-title":"Drug Des Devel Ther."},{"issue":"3","key":"B23-20251101","first-page":"211","article-title":"Hyperuricemia in diarrheal dehydration","volume":"136","author":"Adler","year":"1982","journal-title":"Am J Dis Child."},{"issue":"1","key":"B24-20251101","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s40001-023-01208-1","article-title":"Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA)","volume":"28","author":"Tanaka","year":"2023","journal-title":"Eur J Med Res."},{"issue":"9","key":"B25-20251101","doi-asserted-by":"crossref","first-page":"107730","DOI":"10.1016\/j.isci.2023.107730","article-title":"URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease","volume":"26","author":"Tanaka","year":"2023","journal-title":"iScience."},{"key":"B26-20251101","doi-asserted-by":"crossref","first-page":"101411","DOI":"10.1016\/j.molmet.2021.101411","article-title":"URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice","volume":"55","author":"Tanaka","year":"2022","journal-title":"Mol Metab."},{"key":"B27-20251101","doi-asserted-by":"crossref","first-page":"782677","DOI":"10.3389\/fphys.2021.782677","article-title":"The CXCL1-CXCR2 axis mediates tubular injury in diabetic nephropathy through the regulation of the inflammatory response","volume":"12","author":"Tang","year":"2021","journal-title":"Front Physiol."},{"key":"B28-20251101","doi-asserted-by":"crossref","first-page":"109693","DOI":"10.1016\/j.biopha.2019.109693","article-title":"Inhibition of CXCL1-CXCR2 axis ameliorates cisplatin-induced acute kidney injury by mediating inflammatory response","volume":"122","author":"Liu","year":"2020","journal-title":"Biomed Pharmacother."},{"issue":"10","key":"B29-20251101","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1038\/s41440-023-01391-y","article-title":"Inhibition of the uric acid efflux transporter ABCG2 enhances stimulating effect of soluble uric acid on IL-1\u03b2 production in murine macrophage-like J774.1 cells","volume":"46","author":"Notsu","year":"2023","journal-title":"Hypertens Res."},{"issue":"2","key":"B30-20251101","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1152\/ajpendo.00347.2013","article-title":"NF-\u03baB and STAT1 control CXCL1 and CXCL2 gene transcription","volume":"306","author":"Burke","year":"2014","journal-title":"Am J Physiol Endocrinol Metab."},{"issue":"6","key":"B31-20251101","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1681\/ASN.2006060634","article-title":"Toll-like receptor 4 ligation on intrinsic renal cells contributes to the induction of antibody-mediated glomerulonephritis via CXCL1 and CXCL2","volume":"18","author":"Brown","year":"2007","journal-title":"J Am Soc Nephrol."},{"key":"B32-20251101","doi-asserted-by":"crossref","first-page":"518","DOI":"10.3389\/fphar.2016.00518","article-title":"Identification of febuxostat as a new strong ABCG2 inhibitor: potential applications and risks in clinical situations","volume":"7","author":"Miyata","year":"2016","journal-title":"Front Pharmacol."},{"issue":"8","key":"B33-20251101","doi-asserted-by":"crossref","first-page":"F939","DOI":"10.1152\/ajprenal.00025.2013","article-title":"Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice","volume":"307","author":"Leelahavanichkul","year":"2014","journal-title":"Am J Physiol Renal Physiol."}],"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000000910","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:03:21Z","timestamp":1786478601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000000910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":33,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.34067\/kid.0000000910","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]},"assertion":[{"value":"2025-03-06","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-25","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}