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Research Article
SKIN DISEASE

Sodium channel Nax is a regulator in epithelial sodium homeostasis

Wei Xu, Seok Jong Hong, Aimei Zhong, Ping Xie, Shengxian Jia, Zhong Xie, Michael Zeitchek, Solmaz Niknam-Bienia, Jingling Zhao, D. Marshall Porterfield, D. James Surmeier, Kai P. Leung, Robert D. Galiano, and Thomas A. Mustoe [email protected]
Science Translational Medicine • 4 Nov 2015 • Vol 7, Issue 312 • p. 312ra177 • DOI: 10.1126/scitranslmed.aad0286
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Rubbing sodium in a wound

The skin serves as a critical barrier to the outside world; however, little is known about how this barrier returns to homeostasis after it is disturbed. Water loss occurs during many skin disorders, resulting in an increase in extracellular sodium concentration. Now, Xu et al. report that the sodium channel Nax functions as a sodium sensor that contributes to epithelial homeostasis. Nax, which is present in multiple epithelial tissues and up-regulated in scars, increases sodium flux and induces the downstream production of mediators of epithelial cell proliferation and inflammation that may lead to scar formation. Indeed, blocking Nax in animal models decreases scarring and atopic dermatitis–like symptoms, suggesting that Nax may contribute to epithelial homeostasis.

Abstract

The mechanisms by which the epidermis responds to disturbances in barrier function and restores homeostasis are unknown. With a perturbation of the epidermal barrier, water is lost, resulting in an increase in extracellular sodium concentration. We demonstrate that the sodium channel Nax functions as a sodium sensor. With increased extracellular sodium, Nax up-regulates prostasin, which results in activation of the sodium channel ENaC, resulting in increased sodium flux and increased downstream mRNA synthesis of inflammatory mediators. Nax is present in multiple epithelial tissues, and up-regulation of its downstream genes is found in hypertrophic scars. In animal models, blocking Nax expression results in improvement in scarring and atopic dermatitis–like symptoms, both of which are pathological conditions characterized by perturbations in barrier function. These findings support an important role for Nax in maintaining epithelial homeostasis.
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Supplementary Material

Summary

Fig. S1. Nax immunostaining in keratinocytes.
Fig. S2. Expression of Nax and ENaC-α in mouse tissues (C57BL/6).
Fig. S3. Nax downstream gene expression in human primary keratinocytes, and knockdown and overexpression of Nax in HaCaT cells.
Fig. S4. The skin equivalent models used in the study.
Fig. S5. Immunofluorescence staining of Nax, prostasin, and ENaC-α.
Fig. S6. Change of the intracellular sodium concentrations in HaCaT cells.
Fig. S7. Expression of Nax, prostasin, and ENaC-α in stratified HaCaT cells.
Fig. S8. Cluster analysis of the protein kinase phosphorylation array.
Fig. S9. mRNA expression in WNK1 or p38α knockdown HaCaT cells treated with external serine protease.
Fig. S10. Activation of dermal fibroblasts was modulated by cocultured keratinocytes.
Fig. S11. Expression of prostasin in Nax-DsiRNA– or sham-DsiRNA–treated wounds was detected with its specific antibody and visualized with a fluorescently labeled secondary antibody.
Fig. S12. Inhibition of the Nax pathway by DsiRNA.
Fig. S13. Involvement of PAR-2 in the Nax pathway.
Fig. S14. Knockdown of Nax in HaCaT cells.
Table S1. Sequence information used for RNAi.
Table S2. Differentially expressed genes in wild-type and Nax knockdown keratinocytes under the stimulation with high sodium concentration.
Table S3. Sequence information for qPCR primers.
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Information & Authors

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Published In

Science Translational Medicine
Volume 7 | Issue 312
November 2015

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Copyright © 2015, American Association for the Advancement of Science.

Submission history

Received: 15 July 2015
Accepted: 19 September 2015

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Acknowledgments

We would like to acknowledge M. M. Tamkun from the Department of Biochemical Sciences at the Colorado State University, College of Veterinary Medicine, for the full-length human Nax clone. We thank E. Friedrich in the laboratory, A. Mustoe from the University of North Carolina, and K. Stallcup from Northwestern University for the critical reading of the manuscript. Funding: This study was supported by internal funding from the Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, and in part from the Geneva Foundation a grant to D.J.S. from the JPB Foundation. Author contributions: W.X., S.J.H., D.M.P., D.J.S., K.P.L., R.D.G., and T.A.M. designed the research; W.X., S.J.H., A.Z., S.J., P.X., Z.X., M.Z., J.Z., and S.N.-B. performed the research; D.M.P., D.J.S., and K.P.L. contributed new reagents/analyzed data; and W.X., S.J.H., and T.A.M. wrote the paper. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The microarray data are deposited in the NCBI GEO with a serial record GSE65366.

Authors

Affiliations

Wei Xu*
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Present address: School of Renewable Natural Resources, Agricultural Center, Louisiana State University, Baton Rouge, LA 70820, USA.
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Seok Jong Hong*
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Aimei Zhong
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
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Ping Xie
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Shengxian Jia
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Zhong Xie
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Michael Zeitchek
Department of Agricultural and Biological Engineering, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
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Solmaz Niknam-Bienia
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Jingling Zhao
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Burns, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
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D. Marshall Porterfield
Department of Agricultural and Biological Engineering, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
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D. James Surmeier
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Kai P. Leung
Microbiology Branch, U.S. Army Dental and Trauma Research Detachment, Institute of Surgical Research, JB Fort Sam Houston, San Antonio, TX 78234, USA.
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Robert D. Galiano
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Thomas A. Mustoe‡ [email protected]
Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Notes

*
These authors contributed equally to this work.
‡Corresponding author. E-mail: [email protected]

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