Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation

Nature Medicine volume 18, pages 1112–1117 (2012)Cite this article

Subjects

Abstract

Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na+ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca2+ influx that leads to prostaglandin E2 (PGE2) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation1,2,3. We detected maximum ENaC activation, as indicated by ENaC cleavage4, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE2 production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ENaC-mediated signal transduction events and PGE2 release from mouse EECs.
Figure 2: Involvement of ENaC in decidualization.
Figure 3: Requirement of ENaC for embryo implantation in vivo.
Figure 4: Abnormal ENaC expression in women with IVF failure and working model of ENaC in initiating decidualization.

Similar content being viewed by others

References

  1. Ruan, Y.C., Zhou, W. & Chan, H.C. Regulation of smooth muscle contraction by the epithelium: role of prostaglandins. Physiology (Bethesda) 26, 156–170 (2011).

    CAS  Google Scholar 

  2. Bonventre, J.V. et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622–625 (1997).

    Article  CAS  Google Scholar 

  3. Lim, H. et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 91, 197–208 (1997).

    Article  CAS  Google Scholar 

  4. Kleyman, T.R., Carattino, M.D. & Hughey, R.P. ENaC at the cutting edge: regulation of epithelial sodium channels by proteases. J. Biol. Chem. 284, 20447–20451 (2009).

    Article  CAS  Google Scholar 

  5. Ansell, J.D., Barlow, P.W. & McLaren, A. Binucleate and polyploid cells in the decidua of the mouse. J. Embryol. Exp. Morphol. 31, 223–227 (1974).

    CAS  Google Scholar 

  6. Enders, A.C. & Schlafke, S. Comparative aspects of blastocyst-endometrial interactions at implantation. Ciba Found. Symp. 64, 3–32 (1978).

    Google Scholar 

  7. Parkening, T.A. Apposition of uterine luminal epithelium during implantation in senescent golden hamsters. J. Gerontol. 34, 335–344 (1979).

    Article  CAS  Google Scholar 

  8. Hedlund, K., Nilsson, O., Reinius, S. & Aman, G. Attachment reaction of the uterine luminal epithelium at implantation: light and electron microscopy of the hamster, guinea-pig, rabbit and mink. J. Reprod. Fertil. 29, 131–132 (1972).

    Article  CAS  Google Scholar 

  9. Martin, L., Finn, C.A. & Carter, J. Effects of progesterone and oestradiol-17 β on the luminal epithelium of the mouse uterus. J. Reprod. Fertil. 21, 461–469 (1970).

    Article  CAS  Google Scholar 

  10. Finn, C.A. Endocrine control of endometrial sensitivity during the induction of the decidual cell reaction in the mouse. J. Endocrinol. 36, 239–248 (1966).

    Article  CAS  Google Scholar 

  11. Lejeune, B., Lecocq, R., Lamy, F. & Leroy, F. Changes in the pattern of endometrial protein synthesis during decidualization in the rat. J. Reprod. Fertil. 66, 519–523 (1982).

    Article  CAS  Google Scholar 

  12. Lejeune, B., Van Hoeck, J. & Leroy, F. Transmitter role of the luminal uterine epithelium in the induction of decidualization in rats. J. Reprod. Fertil. 61, 235–240 (1981).

    Article  CAS  Google Scholar 

  13. Almog, B., Shalom-Paz, E., Dufort, D. & Tulandi, T. Promoting implantation by local injury to the endometrium. Fertil. Steril. 94, 2026–2029 (2010).

    Article  Google Scholar 

  14. Salamonsen, L.A. & Nie, G. Proteases at the endometrial-trophoblast interface: their role in implantation. Rev. Endocr. Metab. Disord. 3, 133–143 (2002).

    Article  CAS  Google Scholar 

  15. Salamonsen, L.A., Hannan, N.J. & Dimitriadis, E. Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. Semin. Reprod. Med. 25, 437–444 (2007).

    Article  CAS  Google Scholar 

  16. Sawada, H., Yamazaki, K. & Hoshi, M. Trypsin-like hatching protease from mouse embryos: evidence for the presence in culture medium and its enzymatic properties. J. Exp. Zool. 254, 83–87 (1990).

    Article  CAS  Google Scholar 

  17. Kellenberger, S. & Schild, L. Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol. Rev. 82, 735–767 (2002).

    Article  CAS  Google Scholar 

  18. Yang, J.Z. et al. Differential expression and localization of CFTR and ENaC in mouse endometrium during pre-implantation. Cell Biol. Int. 28, 433–439 (2004).

    Article  CAS  Google Scholar 

  19. Vallet, V., Chraibi, A., Gaeggeler, H.P., Horisberger, J.D. & Rossier, B.C. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 389, 607–610 (1997).

    Article  CAS  Google Scholar 

  20. Fronius, M. & Clauss, W.G. Mechano-sensitivity of ENaC: may the (shear) force be with you. Pflugers Arch. 455, 775–785 (2008).

    Article  CAS  Google Scholar 

  21. Kawabe, A. et al. Production of prostaglandinE2 via bile acid is enhanced by trypsin and acid in normal human esophageal epithelial cells. Life Sci. 75, 21–34 (2004).

    Article  CAS  Google Scholar 

  22. Rastogi, P., Young, D.M. & McHowat, J. Tryptase activates calcium-independent phospholipase A2 and releases PGE2 in airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L925–L932 (2008).

    Article  CAS  Google Scholar 

  23. Orehek, J., Douglas, J.S. & Bouhuys, A. Contractile responses of the guinea-pig trachea in vitro: modification by prostaglandin synthesis–inhibiting drugs. J. Pharmacol. Exp. Ther. 194, 554–564 (1975).

    CAS  Google Scholar 

  24. Donaldson, S.H. et al. Regulation of the epithelial sodium channel by serine proteases in human airways. J. Biol. Chem. 277, 8338–8345 (2002).

    Article  CAS  Google Scholar 

  25. Nesterov, V., Dahlmann, A., Bertog, M. & Korbmacher, C. Trypsin can activate the epithelial sodium channel (ENaC) in microdissected mouse distal nephron. Am. J. Physiol. Renal Physiol. 295, F1052–F1062 (2008).

    Article  CAS  Google Scholar 

  26. Sakoff, J.A. & Murdoch, R.N. The role of calcium in the artificially induced decidual cell reaction in pseudopregnant mice. Biochem. Mol. Med. 57, 81–90 (1996).

    Article  CAS  Google Scholar 

  27. Ruan, Y.C. et al. Regulation of smooth muscle contractility by the epithelium in rat vas deferens: role of ATP-induced release of PGE2. J. Physiol. (Lond.) 586, 4843–4857 (2008).

    Article  CAS  Google Scholar 

  28. Kennedy, T.G., Gillio-Meina, C. & Phang, S.H. Prostaglandins and the initiation of blastocyst implantation and decidualization. Reproduction 134, 635–643 (2007).

    Article  CAS  Google Scholar 

  29. Tsatsanis, C., Androulidaki, A., Venihaki, M. & Margioris, A.N. Signalling networks regulating cyclooxygenase-2. Int. J. Biochem. Cell Biol. 38, 1654–1661 (2006).

    Article  CAS  Google Scholar 

  30. Fouladi Nashta, A.A., Andreu, C.V., Nijjar, N., Heath, J.K. & Kimber, S.J. Role of leukemia inhibitor factor (LIF) in decidualisation of murine uterine stromal cells in vitro. J. Endocrinol. 181, 477–492 (2004).

    Article  CAS  Google Scholar 

  31. Pakrasi, P.L. & Jain, A.K. Cyclooxygenase-2 derived PGE2 and PGI2 play an important role via EP2 and PPARδ receptors in early steps of oil induced decidualization in mice. Placenta 29, 523–530 (2008).

    Article  CAS  Google Scholar 

  32. Yee, G.M. & Kennedy, T.G. Prostaglandin E2, cAMP and cAMP-dependent protein kinase isozymes during decidualization of rat endometrial stromal cells in vitro. Prostaglandins 46, 117–138 (1993).

    Article  CAS  Google Scholar 

  33. Dolphin, A.C. A short history of voltage-gated calcium channels. Br. J. Pharmacol. 147 (suppl. 1), S56–S62 (2006).

    CAS  Google Scholar 

  34. Toth, B. et al. Disorders of implantation—are there diagnostic and therapeutic options? J. Reprod. Immunol. 90, 117–123 (2011).

    Article  CAS  Google Scholar 

  35. Carattino, M.D., Hughey, R.P. & Kleyman, T.R. Proteolytic processing of the epithelial sodium channel gamma subunit has a dominant role in channel activation. J. Biol. Chem. 283, 25290–25295 (2008).

    Article  CAS  Google Scholar 

  36. Chan, L.N. et al. Distribution and regulation of ENaC subunit and CFTR mRNA expression in murine female reproductive tract. J. Membr. Biol. 185, 165–176 (2002).

    Article  CAS  Google Scholar 

  37. Salker, M.S. et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat. Med. 17, 1509–1513 (2011).

    Article  CAS  Google Scholar 

  38. Sugimoto, Y. & Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 282, 11613–11617 (2007).

    Article  CAS  Google Scholar 

  39. Chan, L.N., Wang, X.F., Tsang, L.L. & Chan, H.C. Pyrimidinoceptors-mediated activation of Ca2+-dependent Cl− conductance in mouse endometrial epithelial cells. Biochim. Biophys. Acta 1497, 261–270 (2000).

    Article  CAS  Google Scholar 

  40. Nie, H.G. et al. Regulation of epithelial sodium channels by cGMP/PKGII. J. Physiol. (Lond.) 587, 2663–2676 (2009).

    Article  CAS  Google Scholar 

  41. Strauss, O. & Wienrich, M. Ca2+−conductances in cultured rat retinal pigment epithelial cells. J. Cell. Physiol. 160, 89–96 (1994).

    Article  CAS  Google Scholar 

  42. Braüner, T., Hulser, D.F. & Strasser, R.J. Comparative measurements of membrane potentials with microelectrodes and voltage-sensitive dyes. Biochim. Biophys. Acta 771, 208–216 (1984).

    Article  Google Scholar 

  43. Krötz, F. et al. Membrane-potential-dependent inhibition of platelet adhesion to endothelial cells by epoxyeicosatrienoic acids. Arterioscler. Thromb. Vasc. Biol. 24, 595–600 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by National 973 projects of China (2012CB944900, 2009CB522102, 2010CB945403), Natural Science Foundation of China (No. 30770817; No. 81161120006; No. 31071019), the Fundamental Research Funds for the Central Universities (Ji Nan University), the Focused Investment Scheme and Li Ka Shing Institute of Health Sciences of The Chinese University of Hong Kong, and the Morningside Foundation.

Author information

Author notes

  1. Ye Chun Ruan and Jing Hui Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

    Ye Chun Ruan, Jing Hui Guo, Lai Ling Tsang, Jian Da Dong, Hui Chen, Mei Kuen Yu, Xiaohua Jiang, Xiao Hu Zhang, Kin Lam Fok, Yiu Wa Chung & Hsiao Chang Chan

  2. School of Life Science, Sun Yat-sen University, Guangzhou, China

    Ye Chun Ruan, Jian Da Dong & Wen Liang Zhou

  3. Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics of Ministry of Education of the People's Republic of China, Women′s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xinmei Liu, Runju Zhang & Hefeng Huang

  4. Key Laboratory for Regenerative Medicine (Ji Nan University–The Chinese University of Hong Kong), Ministry of Education of the People's Republic of China, China

    Xiaohua Jiang & Hsiao Chang Chan

  5. Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, China

    Hsiao Chang Chan

Authors
  1. Ye Chun Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Hui Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinmei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Runju Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lai Ling Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian Da Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mei Kuen Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaohua Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiao Hu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kin Lam Fok
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yiu Wa Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hefeng Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wen Liang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hsiao Chang Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.C.C. and Y.C.R.: conception and design; Y.C.R., J.H.G., X.L., R.Z., L.L.T., J.D.D., H.C., M.K.Y., X.J., X.H.Z., K.L.F. and Y.W.C.: experiments and/or data analysis; H.H.: clinical materials and consultancy; W.L.Z.: intellectual input and supervision; Y.C.R. and H.C.C.: article writing with contributions from other authors.

Corresponding authors

Correspondence to Hefeng Huang, Wen Liang Zhou or Hsiao Chang Chan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1 and 2 (PDF 1934 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruan, Y., Guo, J., Liu, X. et al. Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation. Nat Med 18, 1112–1117 (2012). https://doi.org/10.1038/nm.2771

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2771

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing