Prosaposin and its receptors are differentially expressed in the salivary glands of male and female rats

  • Farzana Islam
  • Md. Sakirul Islam Khan
  • Hiroaki Nabeka
  • Shouichiro Saito
  • Xuan Li
  • Tetsuya Shimokawa
  • Kimiko Yamamiya
  • Naoto Kobayashi
  • Seiji Matsuda
Regular Article
  • 110 Downloads

Abstract

Salivary glands produce various neurotrophins that are thought to regulate salivary function during normal and pathological conditions. Prosaposin (PSAP) is a potent neurotrophin found in several tissues and various biological fluids and may play roles in the regulation of salivary function. However, little is known about PSAP in salivary glands. As the functions of salivary glands are diverse based on age and sex, this study examines whether PSAP and its receptors, G protein-coupled receptor 37 (GPR37) and GPR37L1, are expressed in the salivary glands of rats and whether sex and aging affect their expression. Immunohistochemical analysis revealed that PSAP and its receptors were expressed in the major salivary glands of rats, although their expression varied considerably based on the type of gland, acinar cells, age and sex. In fact, PSAP, GPR37 and GPR37L1 were predominantly expressed in granular convoluted tubule cells of the submandibular gland and the intensity of their immunoreactivity was higher in young adult female rats than age-matched male rats, which was more prominent at older ages (mature adult to menopause). On the other hand, weak PSAP, GPR37 and GPR37L1 immunoreactivity was observed mainly in the basal layer of mucous cells of the sublingual gland. Triple label immunofluorescence analysis revealed that PSAP, GPR37 and GPR37L1 were co-localized in the basal layer of acinar and ductal cells in the major salivary glands. The present findings indicate that PSAP and its receptors, GPR37 and GPR37L1, are expressed in the major salivary glands of rats and their immunoreactivities differ considerably with age and sex.

Keywords

Prosaposin Salivary glands Aging Sex Rat 

Notes

Acknowledgements

We would like to thank D. Shimizu for his technical support with confocal imaging. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/zXYQdv

Compliance with ethical standards

All experimental procedures were accomplished in accordance with the ethical regulations and the guide for animal experimentation at Ehime University School of Medicine, Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

441_2018_2835_Fig11_ESM.gif (425 kb)
Supplementary Fig. 1

(GIF 425 kb).

441_2018_2835_MOESM1_ESM.tif (952 kb)
High Resolution Image (TIFF 951 kb).

References

  1. Abdulla AG (2011) Age related changes of submandibular salivary glands (ultrasonographic and structural study). Diyala. J Med 1:53–61Google Scholar
  2. Abdullah MJ (2015) Prevalence of xerostomia in patients attending Shorish dental speciality in Sulaimani city. J Clin Exp Dent 7:e45–e53CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aloe L, Alleva E, Bohm A, Levi-Montalcini R (1986) Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream. Proc Natl Acad Sci U S A 83:6184–6187CrossRefPubMedPubMedCentralGoogle Scholar
  4. Aloe L, Levi-Montalcini R (1980) Comparative studies on testosterone and L-thyroxine effects on the synthesis of nerve growth factor in mouse submaxillary salivary glands. Exp Cell Res 125:15–22CrossRefPubMedGoogle Scholar
  5. Astor FC, Hanft KL, Ciocon JO (1999) Xerostomia: a prevalent condition in the elderly. Ear Nose Throat J 78:476–479PubMedGoogle Scholar
  6. Beutler E, Grabowski GA (2001) Gaucher disease. In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) The metabolic and molecular bases of inherited disease. McGrawHill, New York, pp 3635–3668Google Scholar
  7. Bradova V, Smíd F, Ulrich-Bott B, Roggendorf W, Paton BC, Harzer K (1993) Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease. Hum Genet 92:143–152CrossRefPubMedGoogle Scholar
  8. Brennan MT, Fox PC (1999) Sex differences in primary Sjögren’s syndrome. J Rheumatol 26:2373–2376PubMedGoogle Scholar
  9. Chen J, Saito S, Kobayashi N, Sato K, Terashita T, Shimokawa T, Mominoki K, Miyawaki K, Sano A, Matsuda S (2008) Expression patterns in alternative splicing forms of prosaposin mRNA in the rat facial nerve nucleus after facial nerve transection. Neurosci Res 60:82–94CrossRefPubMedGoogle Scholar
  10. de Moraes JK, Wagner VP, Fonseca FP, Vargas PA, de Farias CB4, Roesler R, Martins MD (2017) Uncovering the role of brain-derived neurotrophic factor/tyrosine kinase receptor B signaling in head and neck malignancies. J Oral Pathol Med 00:1–7Google Scholar
  11. De Vicente JC, Garcia-Suárez O, Esteban I, Santamaria J, Vega JA (1998) Immunohistochemical localization of neurotrophins and neurotrophin receptors in human and mouse salivary glands. Ann Anat 180:157–163CrossRefPubMedGoogle Scholar
  12. De Wilde PC, Baak JP, van Houwelingen JC, Kater L, Slootweg PJ (1986) Morphometric study of histological changes in sublabial salivary glands due to aging process. J Clin Pathol 39:406–417CrossRefPubMedPubMedCentralGoogle Scholar
  13. Durbin PW, Williams MH, Jeung N, Arnold JS (1966) Development of spontaneous mammary tumors over the life-span of the female Charles River (Sprague-Dawley) rat: the influence of ovariectomy, thyroidectomy, and adrenalectomy-ovariectomy. Cancer Res 26:400–411PubMedGoogle Scholar
  14. Ekstrom J, Khosravani N, Castagnola M, Messana I (2012) Saliva and the control of its secretion. In: Ekberg (ed) Dysphagia, medical radiology. Diagmostic imaging. Springer, Berlin, Heidelberg, pp 19–47Google Scholar
  15. Fauchais AL, Boumediene A, Lalloue F, Gondran G, Loustaud-Ratti V, Vidal E, Jauberteau MO (2009) Brain-derived neurotrophic factor and nerve growth factor correlate with T-cell activation in primary Sjogren's syndrome. Scand J Rheumatol 38:50–57CrossRefPubMedGoogle Scholar
  16. Grover CM, More VP, Singh N, Grover S (2014) Crosstalk between hormones and oral health in the mid-life of women: A comprehensive review. J Int Soc Prev Community Dent 4(Suppl 1):S5–S10PubMedPubMedCentralGoogle Scholar
  17. Hipkaeo W, Sakulsak N, Wakayama T, Yamamoto M, Nakaya MA, Keattikunpairoj S, Kurobo M, Iseki S (2008) Coexpression of menin and JunD during the duct cell differentiation in mouse submandibular gland. Tohoku J Exp Med 214:231–245CrossRefPubMedGoogle Scholar
  18. Hineno T, Sano A, Kondoh K, Ueno S, Kakimoto Y, Yoshida K (1991) Secretion of sphingolipid hydrolase activator precursor, prosaposin. Biochem Biophys Res Commun 176:668–674CrossRefPubMedGoogle Scholar
  19. Hiraiwa M, O'Brien JS, Kishimoto Y, Galdzicka M, Fluharty AL, Ginns EI, Martin BM (1993) Isolation, characterization, and proteolysis of human prosaposin, the precursor of saposins (sphingolipid activator proteins). Arch Biochem Biophys 304:110–116CrossRefPubMedGoogle Scholar
  20. Hondermarck H (2012) Neurotrophins and their receptors in breast cancer. Cytokine Growth Factor Rev 23:357–365CrossRefPubMedGoogle Scholar
  21. Kanai K, Nunoya T, Shibuya K, Nakamura T, Tajima M (1998) Variations in effectiveness of antigen retrieval pretreatments for diagnostic immunohistochemistry. Res Vet Sci 64:57–61CrossRefPubMedGoogle Scholar
  22. Kondoh K, Hineno T, Sano A, Kakimoto Y (1991) Isolation and characterization of prosaposin from human milk. Biochem Biophys Res Commun 181:286–292CrossRefPubMedGoogle Scholar
  23. Koochekpour S, Hu S, Vellasco-Gonzalez C, Bernardo R, Azabdaftari G, Zhu G, Zhau HE, Chung LW, Vessella RL (2012) Serum prosaposin levels are increased in patients with advanced prostate cancer. Prostate 72:253–269CrossRefPubMedGoogle Scholar
  24. Koochekpour S, Lee TJ, Wang R, Culig Z, Delorme N, Caffey S, Marrero L, Aguirre J (2007) Prosaposin upregulates AR and PSA expression and activity in prostate cancer cells (LNCaP). Prostate 67:178–189CrossRefPubMedGoogle Scholar
  25. La Sala G, Marazziti D, Di Pietro C, Golini E, Matteoni R, Tocchini-Valentini GP (2015) Modulation of Dhh signaling and altered Sertoli cell function in mice lacking the GPR37-prosaposin receptor. FASEB J 29:2059–2069CrossRefPubMedGoogle Scholar
  26. Li X, Nabeka H, Saito S, Shimokawa T, Khan MSI, Yamamiya K, Shan F, Gao H, Li C, Matsuda S (2017) Expression of prosaposin and its receptors in the rat cerebellum after kainic acid injection. IBRO Rep 2:31–40CrossRefGoogle Scholar
  27. Mathison R (2009) Submandibular salivary gland endocrine secretions and systemic pathophysiological responses. Open Inflam J 2:9–21Google Scholar
  28. Meyer RC, Giddens MM, Schaefer SA, Hall RA (2013) GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin. Proc Natl Acad Sci U S A 110:9529–9534CrossRefPubMedPubMedCentralGoogle Scholar
  29. Mori M, Sumitomo S, Shrestha P, Tanaka S, Takai Y, Shikimori M (2008) Multifunctional role of growth factors or biologically active peptides in salivary glands and saliva. Oral Med Pathol 12:115–123CrossRefGoogle Scholar
  30. Mori M, Takai Y, Kunikata M (1992) Review: biologically active peptides in the submandibular gland—role of the granular convoluted tubule. Acta Histochem Cytochem 25:325–341CrossRefGoogle Scholar
  31. Motta M, Tatti M, Furlan F, Celato A, Di Fruscio G, Polo G, Manara R, Nigro V, Tartaglia M, Burlina A, Salvioli R (2016) Clinical, biochemical and molecular characterization of prosaposin deficiency. Clin Genet 90:220–229CrossRefPubMedGoogle Scholar
  32. Nabeka H, Uematsu K, Takechi H, Shimokawa T, Yamamiya K, Li C, Li C, Doihara T, Saito S, Kobayashi N, Matsuda S (2014) Prosaposin overexpression following kainic acid-induced neurotoxicity. PLoS One 9(12):e110534CrossRefPubMedPubMedCentralGoogle Scholar
  33. Nagler R (2004) Salivary glands and the aging process: mechanistic aspects, health-status and medicinal-efficacy monitoring. Biogerontology 5:223–233CrossRefPubMedGoogle Scholar
  34. Nagler RM, Hershkovich O (2005) Age-related changes in unstimulated salivary function and composition and its relations to medications and oral sensorial complaints. Aging Clin Exp Res 17:358–366CrossRefPubMedGoogle Scholar
  35. O'Brien JS, Carson GS, Seo HC, Hiraiwa M, Kishimoto Y (1994) Identification of prosaposin as a neurotrophic factor. Proc Natl Acad Sci U S A 91:9593–9596CrossRefPubMedPubMedCentralGoogle Scholar
  36. Oosumi H (1990) Diameter and EGF contents of secretory granules in granular convoluted tubule cells of mice submandibular gland. J Jpn Stomatol Soc 39:860–879Google Scholar
  37. Parke AL (2000) Sjögren’s syndrome: a women’s health problem. J Rheumatol Suppl 61:4–5PubMedGoogle Scholar
  38. Phillips CJ, Tandler B, Nagato T (1993) Evolutionary divergence of salivary gland acinar cells: a format for understanding molecular evolution. In: DobrosielskiVergona K (ed) Biology of the salivary glands. CRS press, Boca Raton, pp 39–80Google Scholar
  39. Proctor GB (2016) The physiology of salivary secretion. Periodontol 2000 70:11–25CrossRefGoogle Scholar
  40. Proctor GB, Carpenter GH (2007) Regulation of salivary gland function by autonomic nerves. Auton Neurosci 133:3–18CrossRefPubMedGoogle Scholar
  41. Prodan A, Brand HS, Ligtenberg AJ, Imangaliyev S, Tsivtsivadze E, van der Weijden F, Crielaard W, Keijser BJ, Veerman EC (2015) Interindividual variation, correlations, and sex-related differences in the salivary biochemistry of young healthy adults. Eur J Oral Sci 123:149–157CrossRefPubMedGoogle Scholar
  42. Sahasrabuddhe NA, Barbhuiya MA, Bhunia S, Subbannayya T, Gowda H, Advani J, Shrivastav BR, Navani S, Leal P, Roa JC, Chaerkady R, Gupta S, Chatterjee A, Pandey A, Tiwari PK (2014) Identification of prosaposin and transgelin as potential biomarkers for gallbladder cancer using quantitative proteomics. Biochem Biophys Res Commun 446:863–869CrossRefPubMedPubMedCentralGoogle Scholar
  43. Saruta J, Fujino K, To M, Tsukinoki K (2012) Expression and localization of brain-derived neurotrophic factor (BDNF) mRNA and protein in human submandibular gland. Acta Histochem Cytochem 45:211–218CrossRefPubMedPubMedCentralGoogle Scholar
  44. Sengupta P (2013) The laboratory rat: relating its age with Human's. Int J Prev Med 4:624–630PubMedPubMedCentralGoogle Scholar
  45. Shimokawa T, Nabeka H, Yamamiya K, Wakisaka H, Takeuchi T, Kobayashi N, Matsuda S (2013) Distribution of prosaposin in rat lymphatic tissues. Cell Tissue Res 352:685–693CrossRefPubMedGoogle Scholar
  46. Sun Y, Witte DP, Grabowski GA (1994) Developmental and tissue-specific expression of prosaposin mRNA in murine tissues. Am J Pathol 145:1390–1398PubMedPubMedCentralGoogle Scholar
  47. Tsukinoki K, Saruta J (2012) Role of stress-related brain-derived neurotrophic factor (BDNF) in the rat submandibular gland. Acta Histochem Cytochem 45:261–267CrossRefPubMedPubMedCentralGoogle Scholar
  48. Tsukitani K, Mori M (1986) Immunohistochemistry and radioimmunassay of EGF in submandibular glands of mice treated with secretagogues. Cell Mol Biol 32:677–683PubMedGoogle Scholar
  49. Unuma K, Chen J, Saito S, Kobayashi N, Sato K, Saito K, Wakisaka H, Mominoki K, Sano A, Matsuda S (2005) Changes in expression of prosaposin in the rat facial nerve nucleus after facial nerve transection. Neurosci Res 52:220–227CrossRefPubMedGoogle Scholar
  50. Van Den Berghe L, Sainton K, Gogat K, Marchant D, Dufour E, Bonnel S, Gadin S, Menasche M, Abitbol M (2004) Prosaposin gene expression in normal and dystrophic RCS rat retina. Invest Ophthalmol Vis Sci 45:1297–1305CrossRefGoogle Scholar
  51. Walch ET, Marchetti D (1999) Role of neurotrophins and neurotrophins receptors in the in vitro invasion and heparanase production of human prostate cancer cells. Clin Exp Metastasis 17:307–314CrossRefPubMedGoogle Scholar
  52. Wu Y, Sun L, Zou W, Xu J, Liu H, Wang W, Yun X, Gu J (2012) Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth. Cancer Sci 103:1820–1825CrossRefPubMedGoogle Scholar
  53. Xiao N, Lin Y, Cao H, Sirjani D, Giaccia AJ, Koong AC, Kong CS, Diehn M, Le QT (2014) Neurotrophic factor GDNF promotes survival of salivary stem cells. J Clin Invest 124:3364–3377CrossRefPubMedPubMedCentralGoogle Scholar
  54. Zolotukhin S (2013) Metabolic hormones in saliva: origins and functions. Oral Dis 19:219–229CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Farzana Islam
    • 1
  • Md. Sakirul Islam Khan
    • 1
    • 2
  • Hiroaki Nabeka
    • 1
  • Shouichiro Saito
    • 3
  • Xuan Li
    • 1
  • Tetsuya Shimokawa
    • 1
  • Kimiko Yamamiya
    • 1
  • Naoto Kobayashi
    • 4
  • Seiji Matsuda
    • 1
  1. 1.Department of Anatomy and EmbryologyEhime University Graduate School of MedicineToonJapan
  2. 2.Department of Animal ScienceBangladesh Agricultural UniversityMymensinghBangladesh
  3. 3.Laboratory of Veterinary Anatomy, Faculty of Applied Biological SciencesGifu UniversityGifuJapan
  4. 4.Medical Education CenterEhime University Graduate School of MedicineToonJapan

Personalised recommendations