ArticleThe Journal of investigative dermatology2015
Hydration status regulates sodium flux and inflammatory pathways through epithelial sodium channel (ENaC) in the skin.
Article in The Journal of investigative dermatology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders.Frontiers in immunology · 2020Pooled it
- TRPV4 mediates low-humidity responses in epidermal keratinocytes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Enhancement of Skin Barrier Function Using DYNAMiQ Technology: A Clinical Evaluation.Journal of cosmetic dermatology · 2026Article
- Epithelial-mesenchymal transition in cutaneous fibrosis disease: from mechanisms to therapy.Frontiers in immunology · 2026Review
- Ethacrynic Acid Mitigates Skin Fibrosis through Downregulation of S100 Family Damage-Associated Molecular Pattern Expression in the Epidermis.The Journal of investigative dermatology · 2025Article
- Environmental protein corona on nanoplastics altered the responses of skin keratinocytes and fibroblast cells to the particles.Journal of hazardous materials · 2025Article
- A 30-Min Exposure on Permethrin and Deltamethrin Modifies Ion Transport Pathways in the Skin.Biomolecules · 2024Article
- Associations between serum mineral concentrations and mortality by renal function in the Ludwigshafen Risk and Cardiovascular Health Study.Scientific reports · 2024Article
- The Influence of Retinol Ointment on Rabbit Skin (International journal of molecular sciences · 2024Article
- Cellular response of keratinocytes to the entry and accumulation of nanoplastic particles.Particle and fibre toxicology · 2024Article
- Importance of Stratum Corneum Acidification to Restore Skin Barrier Function in Eczematous Diseases.Annals of dermatology · 2024Review
- Maintaining and Restoring Gradients of Ions in the Epidermis: The Role of Ion and Water Channels in Acute Cutaneous Wound Healing.Advances in wound care · 2023Review
- Chitosan-Glycolic Acid Gel Modification of Chloride Ion Transport in Mammalian Skin: An In Vitro Study.Molecules (Basel, Switzerland) · 2023Article
- Serine protease 35 regulates the fibroblast matrisome in response to hyperosmotic stress.Science advances · 2023Article
- Nickel ions influence the transepithelial sodium transport in the trachea, intestine and skin.Scientific reports · 2023Article
- Simvastatin cream alleviates dermal fibrosis in a rabbit ear hypertrophic scar model.Journal of cosmetic dermatology · 2023Article
- The Impact of Diclofenac Gel on Ion Transport in the Rabbit (Molecules (Basel, Switzerland) · 2023Article
- Role of epithelial sodium channel-related inflammation in human diseases.Frontiers in immunology · 2023Review
- Bioelectric Signaling: Role of Bioelectricity in Directional Cell Migration in Wound Healing.Cold Spring Harbor perspectives in biology · 2022Review
- Pharmaceutical Prophylaxis of Scarring with Emphasis on Burns: A Review of Preclinical and Clinical Studies.Advances in wound care · 2022Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although it is known that the inflammatory response that results from disruption of epithelial barrier function after injury results in excessive scarring, the upstream signals remain unknown. It has also been observed that epithelial disruption results in reduced hydration status and that the use of occlusive dressings that prevent water loss from wounds decreases scar formation. We hypothesized that hydration status changes sodium homeostasis and induces sodium flux in keratinocytes, which result in activation of pathways responsible for keratinocyte-fibroblast signaling and ultimately lead to activation of fibroblasts. Here, we demonstrate that perturbations in epithelial barrier function lead to increased sodium flux in keratinocytes. We identified that sodium flux in keratinocytes is mediated by epithelial sodium channels (ENaCs) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway. Similar changes in signal transduction and sodium flux occur by increased sodium concentration, which simulates reduced hydration, in the media in epithelial cultures or human ex vivo skin cultures. Blockade of ENaC, prostaglandin synthesis, or PGE2 receptors all reduce markers of fibroblast activation and collagen synthesis. In addition, employing a validated in vivo excessive scar model in the rabbit ear, we demonstrate that utilization of either an ENaC blocker or a COX-2 inhibitor results in a marked reduction in scarring. Other experiments demonstrate that the activation of COX-2 in response to increased sodium flux is mediated through the PIK3/Akt pathway. Our results indicate that ENaC responds to small changes in sodium concentration with inflammatory mediators and suggest that the ENaC pathway is a potential target for a strategy to prevent fibrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.