Pflügers Archiv - European Journal of Physiology

, Volume 465, Issue 2, pp 271–281 | Cite as

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

  • Keitaro SatohEmail author
  • Takanori Narita
  • Miwako Matsuki-Fukushima
  • Ken Okabayashi
  • Tatsuro Ito
  • Hidenobu Senpuku
  • Hiroshi Sugiya
Molecular and Cellular Mechanisms of Disease


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.


Salivary glands AQP5 protein Down-regulation Dry mouth Ubiquitin Disease model 



Aquaporin 5


Non-obese diabetic


Severe combined immunodeficiency disease


Sjögren’s syndrome


Bovine serum albumin


Reverse transcription/polymerase chain reaction


Glyceraldehyde-3-phosphate dehydrogenase


β2 microglobulin


Hypoxanthine phosphoribosyl transferase


Sodium dodecyl sulfate


Polyacrylamide gel electrophoresis




Western blot analysis





We thank Prof. Yoshiteru Seo (Dokkyo Medical University) for his helpful advice and discussion. This study was supported by a Dokkyo Medical University Research Grant (#2009-01-3), a Grant-in-Aid for Scientific Research from JSPS (#24580433, #21390506), and MEXT-Supported Program for the Strategic Research Foundation at Private University, 2010–2014.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Keitaro Satoh
    • 1
    Email author
  • Takanori Narita
    • 2
  • Miwako Matsuki-Fukushima
    • 3
  • Ken Okabayashi
    • 2
  • Tatsuro Ito
    • 4
    • 5
  • Hidenobu Senpuku
    • 5
  • Hiroshi Sugiya
    • 2
    • 6
  1. 1.Department of Regulatory PhysiologyDokkyo Medical University School of MedicineShimotsuga-gunJapan
  2. 2.Laboratory of Veterinary Biochemistry, College of Bioresource SciencesNihon UniversityKanagawaJapan
  3. 3.Department of PhysiologyNihon University School of Dentistry at MatsudoChibaJapan
  4. 4.Department of Pediatric DentistryNihon University School of Dentistry at MatsudoChibaJapan
  5. 5.Department of BacteriologyNational Institute of Infectious DiseasesTokyoJapan
  6. 6.Oral Health Science Center Project, hrc8Tokyo Dental CollegeChibaJapan

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