Pflügers Archiv - European Journal of Physiology

, Volume 471, Issue 1, pp 123–136 | Cite as

Systemic network for dietary inorganic phosphate adaptation among three organs

  • Kayo Ikuta
  • Hiroko SegawaEmail author
  • Ai Hanazaki
  • Toru Fujii
  • Ichiro Kaneko
  • Yuji Shiozaki
  • Sawako Tatsumi
  • Yasuko Ishikawa
  • Ken-ichi Miyamoto
Original Article


Inorganic phosphate (Pi) secretion from the salivary glands and dietary Pi are key Pi sources. The regulatory mechanisms of Pi homeostasis in the salivary glands are unknown. We investigated how salivary Pi concentrations are regulated by dietary Pi in mouse models. Dietary manipulation significantly changed the levels of Npt2b protein in the salivary gland ductal cells. In addition, rapid feeding on a high-Pi diet increased the saliva Pi concentrations and led to rapid endocytosis of Npt2b in the apical membranes of the duct cells. Global Npt2b± mice exhibited increased salivary Pi concentrations and intestine-specific deletion of Npt2b after high Pi loading increased the salivary Pi concentrations. These findings indicate that Npt2b levels in the salivary glands affect the salivary Pi concentration and are regulated by dietary Pi. Intestinal Npt2b levels might also affect salivary Pi concentrations as well as renal Pi excretion. These findings suggest Pi is endogenously recycled by salivary Pi secretion, intestinal Pi absorption, and renal Pi excretion.


Phosphate Kidney Intestine Salivary glands Transporter 



We thank the Daiichi-Sankyo Pharmaceutical Co. (Tokyo, Japan) for providing the cevimeline. K.I., H.S., and K-I.M. conceived of and designed the research; K.I., H.S., A.H., T. F., I. K., S.T., and Y.I. performed the experiments; K.I., H.S., and K-I.M. analyzed the data; K.I., and H.S. prepared the figures; K.I., H.S., and K-I.M. drafted the manuscript. The technical assistance of Tomo Mukai, Shohei Sasaki, Ayaka Mori, and Shihoko Yuki is gratefully acknowledged.

Funding information

This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 23689045 to H. Segawa, No. 26293204 to K. Miyamoto), and The Salt Science Research Foundation (Japan).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

424_2018_2242_MOESM1_ESM.pdf (43 kb)
ESM 1 (PDF 43 kb)
424_2018_2242_MOESM2_ESM.pdf (2.5 mb)
ESM 2 (PDF 2563 kb)
424_2018_2242_MOESM3_ESM.pdf (1.1 mb)
ESM 3 (PDF 1091 kb)
424_2018_2242_MOESM4_ESM.pdf (163 kb)
ESM 4 (PDF 162 kb)
424_2018_2242_MOESM5_ESM.pdf (144 kb)
ESM 5 (PDF 143 kb)


  1. 1.
    Amano O, Mizobe K, Bando Y, Sakiyama K (2012) Anatomy and histology of rodent and human major salivary glands: -overview of the Japan salivary gland society-sponsored workshop. Acta Histochem Cytochem 45:241–250. CrossRefGoogle Scholar
  2. 2.
    Aps JK, Martens LC (2005) Review: the physiology of saliva and transfer of drugs into saliva. Forensic Sci Int 150:119–131. CrossRefGoogle Scholar
  3. 3.
    Ba J, Friedman PA (2004) Calcium-sensing receptor regulation of renal mineral ion transport. Cell Calcium 35:229–237CrossRefGoogle Scholar
  4. 4.
    Bandyopadhyay BC, Swaim WD, Sarkar A, Liu X, Ambudkar IS (2012) Extracellular Ca(2+) sensing in salivary ductal cells. J Biol Chem 287:30305–30316. CrossRefGoogle Scholar
  5. 5.
    Baum BJ (1993) Principles of saliva secretion. Ann New York Acad Sci 694:17–23CrossRefGoogle Scholar
  6. 6.
    Block GA, Persky MS, Shamblin BM, Baltazar MF, Singh B, Sharma A, Pergola P, Smits G, Comelli MC (2013) Effect of salivary phosphate-binding chewing gum on serum phosphate in chronic kidney disease. Nephron Clin Pract 123:93–101. CrossRefGoogle Scholar
  7. 7.
    Catalan MA, Nakamoto T, Melvin JE (2009) The salivary gland fluid secretion mechanism. J Med Investig : JMI 56(Suppl):192–196CrossRefGoogle Scholar
  8. 8.
    Davidovich E, Davidovits M, Peretz B, Shapira J, Aframian DJ (2011) Elevated salivary potassium in paediatric CKD patients, a novel excretion pathway. Nephrol Dial Transplant 26:1541–1546. CrossRefGoogle Scholar
  9. 9.
    Hernando N, Myakala K, Simona F, Knopfel T, Thomas L, Murer H, Wagner CA, Biber J (2015) Intestinal depletion of NaPi-IIb/Slc34a2 in mice: renal and hormonal adaptation. J Bone Miner Res 30:1925–1937. CrossRefGoogle Scholar
  10. 10.
    Homann V, Rosin-Steiner S, Stratmann T, Arnold WH, Gaengler P, Kinne RK (2005) Sodium-phosphate cotransporter in human salivary glands: molecular evidence for the involvement of NPT2b in acinar phosphate secretion and ductal phosphate reabsorption. Arch Oral Biol 50:759–768. CrossRefGoogle Scholar
  11. 11.
    Huber K, Roesler U, Holthausen A, Pfeffer E, Breves G (2007) Influence of dietary calcium and phosphorus supply on epithelial phosphate transport in preruminant goats. J Comp Physiol B 177:193–203. CrossRefGoogle Scholar
  12. 12.
    Huber K, Roesler U, Muscher A, Hansen K, Widiyono I, Pfeffer E, Breves G (2003) Ontogenesis of epithelial phosphate transport systems in goats. Am J Phys Regul Integr Comp Phys 284:R413–R421. Google Scholar
  13. 13.
    Humphrey SP, Williamson RT (2001) A review of saliva: normal composition, flow, and function. J Prosthet Dent 85:162–169. CrossRefGoogle Scholar
  14. 14.
    Kondo Y, Nakamoto T, Jaramillo Y, Choi S, Catalan MA, Melvin JE (2015) Functional differences in the acinar cells of the murine major salivary glands. J Dent Res 94:715–721. CrossRefGoogle Scholar
  15. 15.
    Lac G (2001) Saliva assays in clinical and research biology. Pathologie-Biologie 49:660–667CrossRefGoogle Scholar
  16. 16.
    Marks J, Lee GJ, Nadaraja SP, Debnam ES, Unwin RJ (2015) Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon. Phys Rep 3.
  17. 17.
    Miranda-Rius J, Brunet-Llobet L, Lahor-Soler E, Farre M (2015) Salivary secretory disorders, inducing drugs, and clinical management. Int J Med Sci 12:811–824. CrossRefGoogle Scholar
  18. 18.
    Ogbureke KU, Fisher LW (2007) SIBLING expression patterns in duct epithelia reflect the degree of metabolic activity. J Histochem Cytochem 55:403–409. CrossRefGoogle Scholar
  19. 19.
    Ohana E (2015) Transepithelial ion transport across duct cells of the salivary gland. Oral Dis 21:826–835. CrossRefGoogle Scholar
  20. 20.
    Ohi A, Hanabusa E, Ueda O, Segawa H, Horiba N, Kaneko I, Kuwahara S, Mukai T, Sasaki S, Tominaga R, Furutani J, Aranami F, Ohtomo S, Oikawa Y, Kawase Y, Wada NA, Tachibe T, Kakefuda M, Tateishi H, Matsumoto K, Tatsumi S, Kido S, Fukushima N, Jishage K, Miyamoto K (2011) Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b(+)/(−) mice. Am J Physiol Ren Physiol 301:F1105–F1113. CrossRefGoogle Scholar
  21. 21.
    Pan Y, Iwata F, Wang D, Muraguchi M, Ooga K, Ohmoto Y, Takai M, Cho G, Kang J, Shono M, Li XJ, Okamura K, Mori T, Ishikawa Y (2009) Identification of aquaporin-5 and lipid rafts in human resting saliva and their release into cevimeline-stimulated saliva. Biochim Biophys Acta 1790:49–56. CrossRefGoogle Scholar
  22. 22.
    Rehak NN, Cecco SA, Csako G (2000) Biochemical composition and electrolyte balance of “unstimulated” whole human saliva. Clin Chem Lab Med 38:335–343. Google Scholar
  23. 23.
    Romanenko VG, Nakamoto T, Catalan MA, Gonzalez-Begne M, Schwartz GJ, Jaramillo Y, Sepulveda FV, Figueroa CD, Melvin JE (2008) Clcn2 encodes the hyperpolarization-activated chloride channel in the ducts of mouse salivary glands. Am J Physiol Gastrointest Liver Physiol 295:G1058–G1067. CrossRefGoogle Scholar
  24. 24.
    Roussa E (2011) Channels and transporters in salivary glands. Cell Tissue Res 343:263–287. CrossRefGoogle Scholar
  25. 25.
    Savica V, Calo LA, Santoro D, Monardo P, Santoro G, Muraca U, Davis PA, Bellinghieri G (2011) Salivary glands: a new player in phosphorus metabolism. J Ren Nutr 21:39–42. CrossRefGoogle Scholar
  26. 26.
    Schneyer LH, Young JA, Schneyer CA (1972) Salivary secretion of electrolytes. Physiol Rev 52:720–777CrossRefGoogle Scholar
  27. 27.
    Thaysen JH, Thorn NA, Schwartz IL (1954) Excretion of sodium, potassium, chloride and carbon dioxide in human parotid saliva. Am J Phys 178:155–159. CrossRefGoogle Scholar
  28. 28.
    Thorens B, Sarkar HK, Kaback HR, Lodish HF (1988) Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and beta-pancreatic islet cells. Cell 55:281–290CrossRefGoogle Scholar
  29. 29.
    Vayro S, Kemp R, Beechey RB, Shirazi-Beechey S (1991) Preparation and characterization of basolateral plasma-membrane vesicles from sheep parotid glands. Mechanisms of phosphate and D-glucose transport. The Biochem J 279(Pt 3):843–848CrossRefGoogle Scholar
  30. 30.
    Wagner CA, Rubio-Aliaga I, Hernando N (2017) Renal phosphate handling and inherited disorders of phosphate reabsorption: an update. Pediatr Nephrol.

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular Nutrition, Institute of Biomedical SciencesUniversity of Tokushima Graduate SchoolTokushima CityJapan
  2. 2.Department of Medical Pharmacology, Institute of Biomedical SciencesUniversity of Tokushima Graduate SchoolTokushimaJapan

Personalised recommendations