Urea uptake enhances barrier function and antimicrobial defense in humans by regulating epidermal gene expression
Open accessAbstract
Urea is an endogenous metabolite, known to enhance stratum corneum hydration. Yet, topical urea anecdotally also improves permeability barrier function, and it appears to exhibit antimicrobial activity. Hence, we hypothesized that urea is not merely a passive metabolite, but a small-molecule regulator of epidermal structure and function. In 21 human volunteers, topical urea improved barrier function in parallel with enhanced antimicrobial peptide (AMP; LL-37 and β-defensin-2) expression. Urea stimulates the expression of, and is transported into, keratinocytes by two urea transporters (UTs), UT-A1 and UT-A2, and by aquaporins 3, 7, and 9. Inhibitors of these UTs block the downstream biological effects of urea, which include increased mRNA and protein levels of (i) transglutaminase-1, involucrin, loricrin, and filaggrin, (ii) epidermal lipid synthetic enzymes, and (iii) cathelicidin/LL-37 and β-defensin-2. Finally, we explored the potential clinical utility of urea, showing that topical urea applications normalized both barrier function and AMP expression in a murine model of atopic dermatitis. Together, these results show that urea is a small-molecule regulator of epidermal permeability barrier function and AMP expression after transporter uptake, followed by gene regulatory activity in normal epidermis, with potential therapeutic applications in diseased skin.
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Patients' cells showed enhanced expression of AQP9.
“Among them, patients’ cells showed the enhanced expression of AQP9, a member of the family of water-selective membrane channels that play a role both in antimicrobial defense and skin barrier permeability [144].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [144]
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- Authors
- Grether-Beck, S., Felsner, I., Brenden, H., Kohne, Z., Majora, M., Marini, A., Jaenicke, T., Rodriguez-Martin, M., Trullas, C., Hupe, M., Elias, P. M., & Krutmann, J.
- Affiliations
- Leibniz Institute of Environmental Medicine (DE)
- San Francisco VA Medical Center (US)
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 132
- Issue
- 6
- Pages
- 1561-1572
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC3352965
- OpenAlex
- W2147701916
- Cited by
- 180
- References
- 67
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 9 · 2021: 13 · 2020: 13 · 2019: 8 · 2018: 13 · 2017: 9 · 2016: 16 · 2015: 19 · 2014: 25 · 2013: 11 · 2012: 6
- FWCI
- 24.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-19098, R01AR019098)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- urea, skin permeability barrier, antimicrobial peptides, LL-37, human beta-defensin 2, cathelicidin, urea transporter, UT-A1, aquaporins, keratinocytes, epidermal gene expression, filaggrin, involucrin, loricrin, transglutaminase 1, epidermal lipids, atopic dermatitis, topical urea
- MeSH terms
- Epidermal Cells, Filaggrin Proteins, Urea Transporters, Adult, Animals, Cell Differentiation, Cell Membrane Permeability, Dermatitis, Atopic, Epidermis, Female, Gene Expression Regulation, Humans, Male, Mice, Hairless, Middle Aged, Urea, Water, Keratinocytes, Aquaporins, Antimicrobial Cationic Peptides, Membrane Transport Proteins, Mice, Aquaporin 3, Young Adult, Primary Cell Culture
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