title: Urea uptake enhances barrier function and antimicrobial defense in humans by regulating epidermal gene expression.
abstract: 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.
authors.affiliation: Institut fuer Umweltmedizinische Forschung, Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany. Grether-Beck@uni-duesseldorf.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Grether-Beck
authors.forename: Ingo
authors.initials: I
authors.lastname: Felsner
authors.forename: Heidi
authors.initials: H
authors.lastname: Brenden
authors.forename: Zippora
authors.initials: Z
authors.lastname: Kohne
authors.forename: Marc
authors.initials: M
authors.lastname: Majora
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marini
authors.forename: Thomas
authors.initials: T
authors.lastname: Jaenicke
authors.forename: Marina
authors.initials: M
authors.lastname: Rodriguez-Martin
authors.forename: Carles
authors.initials: C
authors.lastname: Trullas
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
mesh_terms: D000328:Adult; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D051400:Aquaporin 3 / Q000235:genetics / Q000378:metabolism; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D008875:Middle Aged; D061251:Primary Cell Culture; D014508:Urea / Q000493:pharmacokinetics*; D014867:Water / Q000378:metabolism; D055815:Young Adult; D000096982:Urea Transporters
chemical_list: D023181:Antimicrobial Cationic Peptides; D051400:Aquaporin 3; D020346:Aquaporins; D000091344:Filaggrin Proteins; D026901:Membrane Transport Proteins; D014508:Urea; D014867:Water; D000096982:Urea Transporters; C496027:AQP3 protein, human; C114141:AQP7 protein, human; C109669:AQP9 protein, human; C000717249:FLG protein, human