αvβ6 integrin regulates renal fibrosis and inflammation in Alport mouse
αvβ6 integrin regulates renal fibrosis and inflammation in Alport mouse
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DOI：
10.2353/ajpath.2007.060158
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发表时间：
2007-01-01
影响因子：
6
通讯作者：
Violette, Shelia M.
中科院分区：
文献类型：
--
作者：
Hahm, Kyungmin;Lukashev, Matvey E.;Violette, Shelia M.
转化生长因子(TGF)- β诱导的整合素α v β 6在上皮重塑部位优先表达，并已被证明结合并激活潜在前体TGF- β。本研究表明，在膜性肾小球肾炎、糖尿病、IgA肾病、good牧草综合征和Alport综合征的肾上皮中，α v β 6过表达。为了评估α v β 6在肾脏疾病中的潜在调节作用，我们研究了功能阻断α v β 6单克隆抗体（mab）和β 6亚基基因消融对Col4A3（-/-）小鼠（Alport综合征小鼠模型）肾纤维化的影响。α v β 6在Alport小鼠肾脏中的表达主要见于皮质小管上皮。并与纤维化的进展相关。用α v β 6阻断单抗治疗可抑制活化成纤维细胞的积累和间质胶原基质的沉积。在β 6缺乏的Alport小鼠中观察到类似的肾纤维化抑制作用。肾脏组织的转录谱分析显示，α v β 6阻断单抗显著抑制了纤维化和炎症介质表达的疾病相关变化。重组可溶性tgf - β RII处理产生了类似的转录调节模式，表明α v β 6和tgf - β具有共同的调节功能。这些发现表明，α v β 6可以促进肾纤维化的调节，并提示这种整合素是一种潜在的治疗靶点。
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.