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However, the role of FoxO1 in the salivary gland has not yet been elucidated. In this study, we discovered that FoxO1 and aquaporin 5 (AQP5) are both significantly downregulated in the patients with primary Sj\u00f6gren syndrome, an autoimmune disease accompanying salivary gland dysfunction. Pharmacologic or genetic perturbation of FoxO1 in the rat salivary gland acinar cell line, SMG-C6, induced a significant downregulation of AQP5 expression, as observed in clinical specimens. There was a strong correlation between FoxO1 and AQP5 expression because FoxO1 is a direct regulator of AQP5 expression in salivary gland acinar cells through its interaction with the promoter region of AQP5. Serial injection of a FoxO1 inhibitor into mice induced a reduction of AQP5 expression in submandibular glands and, consequently, hyposalivation, which is one of the major clinical symptoms of primary Sj\u00f6gren syndrome. However, there was no sign of inflammation or cell damage in the submandibular glands harvested from mice treated with the FoxO1 inhibitor. In conclusion, our findings indicate that FoxO1 in salivary gland tissue acts as a direct regulator of AQP5 expression. Thus, downregulation of FoxO1 observed in primary Sj\u00f6gren syndrome is a putative mechanism for hyposalivation without the involvement of previously reported soluble factors in primary Sj\u00f6gren syndrome patient sera.<\/jats:p>","DOI":"10.1177\/00220345211003490","type":"journal-article","created":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T04:58:57Z","timestamp":1618030737000},"page":"1281-1288","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":11,"title":["FoxO1 as a Regulator of Aquaporin 5 Expression in the Salivary Gland"],"prefix":"10.1177","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9710-4604","authenticated-orcid":false,"given":"S.M.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu, Republic of 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