{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T02:37:13Z","timestamp":1785551833010,"version":"3.56.0"},"reference-count":25,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,26]],"date-time":"2019-12-26T00:00:00Z","timestamp":1577318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regional project POR Puglia Innonetwork","award":["H6GG787"],"award-info":[{"award-number":["H6GG787"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic drug would be preferable over a conventional diuretic. The clinical efficacy of vaptans is in principle due to impaired vasopressin-regulated water reabsorption via the water channel aquaporin-2 (AQP2). Here, the effect of lixivaptan\u2014a novel selective V2R antagonist\u2014on the vasopressin-cAMP\/PKA signaling cascade was investigated in mouse renal collecting duct cells expressing AQP2 (MCD4) and the human V2R. Compared to tolvaptan\u2014a selective V2R antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia\u2014lixivaptan has been predicted to be less likely to cause liver injury. In MCD4 cells, clinically relevant concentrations of lixivaptan (100 nM for 1 h) prevented dDAVP-induced increase of cytosolic cAMP levels and AQP2 phosphorylation at ser-256. Consistent with this finding, real-time fluorescence kinetic measurements demonstrated that lixivaptan prevented dDAVP-induced increase in osmotic water permeability. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of lixivaptan and suggest that lixivaptan has the potential to become a safe and effective therapy for the treatment of disorders characterized by high plasma vasopressin concentrations and water retention.<\/jats:p>","DOI":"10.3390\/ijms21010183","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T05:37:08Z","timestamp":1577425028000},"page":"183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Lixivaptan, a New Generation Diuretic, Counteracts Vasopressin-Induced Aquaporin-2 Trafficking and Function in Renal Collecting Duct Cells"],"prefix":"10.3390","volume":"21","author":[{"given":"Annarita","family":"Di Mise","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Venneri","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3118-5813","authenticated-orcid":false,"given":"Marianna","family":"Ranieri","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Centrone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Palladio Biosciences, Inc., Newtown, PA 18940, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Tamma","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1097\/MNH.0b013e328364000d","article-title":"New insights into regulated aquaporin-2 function","volume":"22","author":"Fenton","year":"2013","journal-title":"Curr. 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