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Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse.

The American journal of pathology (2007-01-04)
Kyungmin Hahm, Matvey E Lukashev, Yi Luo, William J Yang, Brian M Dolinski, Paul H Weinreb, Kenneth J Simon, Li Chun Wang, Diane R Leone, Roy R Lobb, Donald J McCrann, Normand E Allaire, Gerald S Horan, Agnes Fogo, Raghu Kalluri, Charles F Shield, Dean Sheppard, Humphrey A Gardner, Shelia M Violette
RÉSUMÉ

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.

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Anti-Integrin alphaV Antibody, CT, Intracellular, serum, Chemicon®