αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse
Open accessAbstract
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.
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A feedforward mechanism involving acute phase cytokines, IL-17A, and TGF-β is responsible for fibrosis following acute tissue injury.
“suggesting a feedforward mechanism involving acute phase cytokines, IL-17A, and TGF-β is responsible for the development of fibrosis following acute tissue injury109,110,123”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [109]
IL-17A is a key inducer of fibrosis in several organ systems, including lung, liver, kidney, heart, and skin.
“The pro-inflammatory cytokine IL-17A was identified as a key inducer of fibrosis in several different organ systems, including the lung, liver, kidney, heart, and skin109–114”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [109]
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References 54 · Cited by 190
Research works printed but not linked: 2
- Yokosaki Y, Monis H, Chen A, Sheppard D: Differential effects of the integrins alpha9beta1, alphavbeta3, and alphavbeta6 on cell prolif- erative responses to tenascin: roles of the beta subunit extracellular and cytoplasmic domains. J Biol Chem 1996, 271:24144 -24150
- Annes JP, Rifkin DB, Munger JS: The integrin ␣v6 binds and acti- vates latent TGF3. FEBS Lett 2002, 511:65-68
- Authors
- Hahm, K., Lukashev, M. E., Luo, Y., Yang, W. J., Dolinski, B. M., Weinreb, P. H., Simon, K. J., Chun Wang, L., Leone, D. R., Lobb, R. R., McCrann, D. J., Allaire, N. E., Horan, G. S., Fogo, A., Kalluri, R., Shield, C. F., Sheppard, D., Gardner, H. A., & Violette, S. M.
- Affiliations
- Biogen (United States) (US)
- Vanderbilt University (US)
- Beth Israel Deaconess Medical Center (US)
- University of Kansas (US)
- University of California, San Francisco (US)
- Corresponding author
- Violette, Shelia M.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2007-01
- Volume
- 170
- Issue
- 1
- Pages
- 110-125
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1762706
- OpenAlex
- W2050921789
- Cited by
- 190
- References
- 54
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 9 · 2019: 11 · 2018: 11 · 2017: 10 · 2016: 12 · 2015: 10 · 2014: 13 · 2013: 9 · 2012: 21
- FWCI
- 7.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biogen
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-55001, R01DK055001)
- Lawrence Berkeley National Laboratory
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- renal fibrosis, renal inflammation, Alport syndrome, TGF-beta, monoclonal antibodies, kidney epithelium, tubular epithelial cells, fibroblast activation, collagen deposition, gene expression profiling, therapeutic target
- MeSH terms
- Animals, Antigens, Neoplasm, Disease Models, Animal, Extracellular Matrix, Fibroblasts, Fibrosis, Humans, Immunohistochemistry, Kidney, Nephritis, Hereditary, Up-Regulation, Integrins, Transforming Growth Factor beta, Mice, Knockout, Antibodies, Blocking, NIH 3T3 Cells, Mice
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