title: E2f1-deficient NOD/SCID mice have dry mouth due to a change of acinar/duct structure and the down-regulation of AQP5 in the salivary gland.
abstract: Non-obese diabetic (NOD) mice have been used as a model for dry mouth. NOD mice lacking the gene encoding E2f1, a transcription factor, develop hyposalivation more rapidly progressively than control NOD mice. However, the model mice are associated with an underlying disease such as diabetes. We have now established E2f1-deficient NOD/severe combined immunodeficiency disease (NOD/SCID.E2f1(-/-)) mice to avoid the development of diabetes (Matsui-Inohara et al., Exp Biol Med (Maywood) 234(12):1525-1536, 2009). In this study, we investigated the pathophysiological features of dry mouth using NOD/SCID.E2f1(-/-) mice. In NOD/SCID.E2f1(-/-) mice, the volume of secreted saliva stimulated with pilocarpine is about one third that of control NOD/SCID mice. In behavioral analysis, NOD/SCID.E2f1(-/-) mice drank plenty of water when they ate dry food, and the frequency and time of water intake were almost double compared with control NOD/SCID mice. Histological analysis of submandibular glands with hematoxylin-eosin stain revealed that NOD/SCID.E2f1(-/-) mice have more ducts than NOD/SCID mice. In western blot analysis, the expression of aquaporin 5 (AQP5), a marker of acinar cells, in parotid and in submandibular glands of NOD/SCID.E2f1(-/-) mice was lower than in NOD/SCID mice. Immunohistochemical analysis of parotid and submandibular acini revealed that the localization of AQP5 in NOD/SCID.E2f1(-/-) mice differs from that in NOD/SCID mice; AQP5 was leaky and diffusively localized from the apical membrane to the cytosol in NOD/SCID.E2f1(-/-) mice. The ubiquitination of AQP5 was detected in submandibular glands of NOD/SCID.E2f1(-/-) mice. These findings suggest that the change of acinar/duct structure and the down-regulation of AQP5 in the salivary gland cause the pathogenesis of hyposalivation in NOD/SCID.E2f1(-/-) mice.
authors.affiliation: Department of Regulatory Physiology, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga-gun, Tochigi, Japan. k-satoh@dokkyomed.ac.jp
authors.forename: Keitaro
authors.initials: K
authors.lastname: Satoh
authors.forename: Takanori
authors.initials: T
authors.lastname: Narita
authors.forename: Miwako
authors.initials: M
authors.lastname: Matsuki-Fukushima
authors.forename: Ken
authors.initials: K
authors.lastname: Okabayashi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ito
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Senpuku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiya
mesh_terms: D061354:Acinar Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051402:Aquaporin 5 / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D004326:Drinking; D050687:E2F1 Transcription Factor / Q000235:genetics*; D015870:Gene Expression; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010306:Parotid Gland / Q000378:metabolism / Q000473:pathology; D010862:Pilocarpine / Q000494:pharmacology; D018987:Salivary Ducts / Q000378:metabolism* / Q000473:pathology; D012472:Salivation / Q000187:drug effects / Q000235:genetics; D013363:Submandibular Gland / Q000378:metabolism / Q000473:pathology; D054875:Ubiquitination; D014987:Xerostomia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C496038:Aqp5 protein, mouse; D051402:Aquaporin 5; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D010862:Pilocarpine