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

Hahm K, Lukashev ME, Luo Y, Yang WJ, Dolinski BM, Weinreb PH, Simon KJ, Chun Wang L, Leone DR, Lobb RR, McCrann DJ, Allaire NE, Horan GS, Fogo A, Kalluri R, Shield CF, Sheppard D, Gardner HA, Violette SM
Am J Pathol. 2007 170 (1): 110-25

PMID: 17200187 · PMCID: PMC1762706 · 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.

MeSH Terms (17)

Animals Antibodies, Blocking Antigens, Neoplasm Disease Models, Animal Extracellular Matrix Fibroblasts Fibrosis Humans Immunohistochemistry Integrins Kidney Mice Mice, Knockout Nephritis, Hereditary NIH 3T3 Cells Transforming Growth Factor beta Up-Regulation

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