Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse.
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.
Hahm
Kyungmin
K
Department of Exploratory Biology, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
Lukashev
Matvey E
ME
Luo
Yi
Y
Yang
William J
WJ
Dolinski
Brian M
BM
Weinreb
Paul H
PH
Simon
Kenneth J
KJ
Chun Wang
Li
L
Leone
Diane R
DR
Lobb
Roy R
RR
McCrann
Donald J
DJ
Allaire
Normand E
NE
Horan
Gerald S
GS
Fogo
Agnes
A
Kalluri
Raghu
R
Shield
Charles F
CF
Sheppard
Dean
D
Gardner
Humphrey A
HA
Violette
Shelia M
SM
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
D019138:Antibodies, Blocking; D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6