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(American Journal of Pathology. 2007;170:110-125.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060158

vß6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

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, III^||, Dean Sheppard^**, Humphrey A. Gardner^* and Shelia M. Violette^*

From the Departments of Exploratory Biology, Fibrosis, Protein Chemistry, Gene Discovery, Molecular Profiling, and Research Pathology,^* Biogen Idec, Cambridge, Massachusetts; the Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; the Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts; the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology,^¶ Boston, Massachusetts; the Department of Surgery,|| University of Kansas School of Medicine, Wichita, Kansas; and the Lung Biology Center,^** University of California San Francisco, San Francisco, California

The transforming growth factor (TGF)-ß-inducible integrin vß6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-ß. Herein, we show that vß6 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 vß6 in renal disease, we studied the effects of function-blocking vß6 monoclonal antibodies (mAbs) and genetic ablation of the ß6 subunit on kidney fibrosis in Col4A3^–/– mice, a mouse model of Alport syndrome. Expression of vß6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with vß6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in ß6-deficient Alport mice. Transcript profiling of kidney tissues showed that vß6-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-ß RII treatment, suggesting shared regulatory functions of vß6 and TGF-ß. These findings demonstrate that vß6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

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