Urea uptake enhances barrier function and antimicrobial defense in humans by regulating epidermal gene expression

J Invest Dermatol. 2012 Jun;132(6):1561-72. doi: 10.1038/jid.2012.42. Epub 2012 Mar 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antimicrobial Cationic Peptides / genetics*
  • Antimicrobial Cationic Peptides / metabolism
  • Aquaporin 3 / genetics
  • Aquaporin 3 / metabolism
  • Aquaporins / genetics
  • Aquaporins / metabolism
  • Cell Differentiation / physiology
  • Cell Membrane Permeability / drug effects*
  • Cell Membrane Permeability / physiology
  • Dermatitis, Atopic / drug therapy*
  • Dermatitis, Atopic / metabolism
  • Dermatitis, Atopic / physiopathology
  • Epidermal Cells
  • Epidermis / metabolism*
  • Female
  • Filaggrin Proteins
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Humans
  • Keratinocytes / cytology
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Hairless
  • Middle Aged
  • Primary Cell Culture
  • Urea / pharmacokinetics*
  • Urea Transporters
  • Water / metabolism
  • Young Adult


  • AQP3 protein, human
  • AQP7 protein, human
  • AQP9 protein, human
  • Antimicrobial Cationic Peptides
  • Aquaporins
  • FLG protein, human
  • Filaggrin Proteins
  • Membrane Transport Proteins
  • Water
  • Aquaporin 3
  • Urea