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It is necessary to develop new type of diuretics to treat hyponatremia without losing electrolytes. Urea transporters (UT) play an important role in the urine concentrating process and have been proved as a novel diuretic target. In this study, rat and mouse syndromes of inappropriate antidiuretic hormone secretion (SIADH) models were constructed and analyzed to determine if UTs are a promising drug target for treating hyponatremia. Experimental results showed that 100\u2009mg\/kg UT inhibitor 25a significantly increased serum osmolality (from 249.83\u2009\u00b1\u20095.95 to 294.33\u2009\u00b1\u20093.90\u2009mOsm\/kg) and serum sodium (from 114\u2009\u00b1\u20092.07 to 136.67\u2009\u00b1\u20093.82\u2009mmol\/L) respectively in hyponatremia rats by diuresis. Serum chemical examination showed that 25a neither caused another electrolyte imbalance nor influenced the lipid metabolism. Using UT\u2010A1 and UT\u2010B knockout mouse SIADH model, it was found that serum osmolality and serum sodium were lowered much less in UT\u2010A1 knockout mice than in UT\u2010B knockout mice, which suggest UT\u2010A1 is a better therapeutic target than UT\u2010B to treat hyponatremia. This study provides a proof of concept that UT\u2010A1 is a diuretic target for SIADH\u2010induced hyponatremia and UT\u2010A1 inhibitors might be developed into new diuretics to treat hyponatremia.<\/jats:p>","DOI":"10.1096\/fj.202400555rr","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T15:45:02Z","timestamp":1719416702000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Urea transporter\n                    <scp>UT<\/scp>\n                    \u2010\n                    <scp>A1<\/scp>\n                    as a novel drug target for hyponatremia"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3563-6793","authenticated-orcid":false,"given":"Nannan","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0307-8622","authenticated-orcid":false,"given":"Hang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4142-7196","authenticated-orcid":false,"given":"Shuyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2755-4719","authenticated-orcid":false,"given":"Yue","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1434-1458","authenticated-orcid":false,"given":"Yi","family":"Ying","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2675-8277","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Anti\u2010Infective Drug Development Sunshine Lake Pharma Co., Ltd.  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