Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse

Am J Pathol. 2007 Jan;170(1):110-25. doi: 10.2353/ajpath.2007.060158.


The transforming growth factor (TGF)-beta-inducible integrin alpha v beta6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-beta. Herein, we show that alpha v beta6 is overexpressed in human kidney epithelium in membranous glomerulonephritis, diabetes mellitus, IgA nephropathy, Goodpasture's syndrome, and Alport syndrome renal epithelium. To assess the potential regulatory role of alpha v beta6 in renal disease, we studied the effects of function-blocking alpha v beta6 monoclonal antibodies (mAbs) and genetic ablation of the beta6 subunit on kidney fibrosis in Col4A3-/- mice, a mouse model of Alport syndrome. Expression of alpha v beta6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with alpha v beta6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in beta6-deficient Alport mice. Transcript profiling of kidney tissues showed that alpha v beta6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-beta RII treatment, suggesting shared regulatory functions of alpha v beta6 and TGF-beta. These findings demonstrate that alpha v beta6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Blocking / immunology
  • Antibodies, Blocking / pharmacology
  • Antigens, Neoplasm / biosynthesis*
  • Antigens, Neoplasm / immunology
  • Disease Models, Animal
  • Extracellular Matrix / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis
  • Humans
  • Immunohistochemistry
  • Integrins / antagonists & inhibitors
  • Integrins / biosynthesis*
  • Integrins / immunology
  • Kidney / metabolism
  • Kidney / pathology
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nephritis, Hereditary / drug therapy
  • Nephritis, Hereditary / etiology
  • Nephritis, Hereditary / metabolism*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation


  • Antibodies, Blocking
  • Antigens, Neoplasm
  • Integrins
  • Transforming Growth Factor beta
  • integrin alphavbeta6