{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T15:24:30Z","timestamp":1782833070539,"version":"3.54.5"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1I1A1A01069274"],"award-info":[{"award-number":["NRF-2020R1I1A1A01069274"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium\/kg dry food) was administered for 2 weeks. Duloxetine (50 mg\/kg\/day) and tolvaptan (10 mg\/kg\/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia.<\/jats:p>","DOI":"10.3390\/life14081012","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T03:49:36Z","timestamp":1723693776000},"page":"1012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Duloxetine-Induced Antidiuresis in Rats with Lithium-Induced Nephrogenic Diabetes Insipidus"],"prefix":"10.3390","volume":"14","author":[{"given":"Sua","family":"Kim","sequence":"first","affiliation":[{"name":"Biomedical Research Institute, Hanyang University College of Medicine, 222-1 Wansimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chor Ho","family":"Jo","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, Hanyang University College of Medicine, 222-1 Wansimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8445-9892","authenticated-orcid":false,"given":"Gheun-Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, Hanyang University College of Medicine, 222-1 Wansimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea"},{"name":"Department of Internal Medicine, Hanyang University College of Medicine, 222-1 Wansimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s00702-021-02369-1","article-title":"Psychotropic drug-induced hyponatremia: Results from a drug surveillance program-an update","volume":"128","author":"Seifert","year":"2021","journal-title":"J. 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