alpha v beta 6 integrin regulates renal fibrosis and inflammation in Alport mouse

The transforming growth factor (TGF)-beta-inducible integrin alpha v beta 6 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 beta 6 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 beta 6 in renal disease, we studied the effects of function-blocking alpha v beta 6 monoclonal antibodies (mAbs) and genetic ablation of the beta 6 subunit on kidney fibrosis in Col4A3(-/-) mice, a mouse model of Alport syndrome. Expression of alpha v beta 6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial. cells and in correlation with the progression of fibrosis. Treatment with alpha v beta 6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in beta 6-deficient Alport mice. Transcript profiling of kidney tissues showed that alpha v beta 6-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 beta 6 and TGF-beta. These findings demonstrate that alpha v beta 6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.