title: Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse.
abstract: 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.
authors.affiliation: Department of Exploratory Biology, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Hahm
authors.forename: Matvey E
authors.initials: ME
authors.lastname: Lukashev
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: William J
authors.initials: WJ
authors.lastname: Yang
authors.forename: Brian M
authors.initials: BM
authors.lastname: Dolinski
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simon
authors.forename: Li
authors.initials: L
authors.lastname: Chun Wang
authors.forename: Diane R
authors.initials: DR
authors.lastname: Leone
authors.forename: Roy R
authors.initials: RR
authors.lastname: Lobb
authors.forename: Donald J
authors.initials: DJ
authors.lastname: McCrann
authors.forename: Normand E
authors.initials: NE
authors.lastname: Allaire
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Horan
authors.forename: Agnes
authors.initials: A
authors.lastname: Fogo
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Charles F
authors.initials: CF
authors.lastname: Shield
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Humphrey A
authors.initials: HA
authors.lastname: Gardner
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000276:immunology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009394:Nephritis, Hereditary / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6