Renal fibrosis - Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells
Renal fibrosis - Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells
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DOI：
10.1016/s0002-9440(10)61150-9
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发表时间：
2002-06-01
影响因子：
6
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Zeisberg, M;Maeshima, Y;Kalluri, R
在慢性肾脏疾病的发展过程中，肾小管基底膜和间质基质的组成会发生质的和量的变化。转化生长因子-β(1)介导的肾小管上皮细胞(TECs)活化被认为是肾小管间质纤维化进展的关键因素。为了进一步了解与肾纤维化相关的发病机制，我们开发了一种使用肾基底膜的体外Boyden小室系统，该系统部分模拟了健康和疾病期间TECs的体内条件。用转化生长因子-β(1)-上皮生长因子直接刺激TECs可增加牛TBM制剂的迁移能力。这与基质金属蛋白酶(MMPs)的产生增加有关，即MMP2和MMP9。转化生长因子-β(1)-EGF或I型胶原的间接趋化刺激不足以诱导未经处理的TECs在牛TBM制剂中的迁移，提示基底膜的完整性和组成在保护TECs免受间质纤维化刺激方面起着重要作用。此外，用Col-3抑制剂中和MMPs显著降低了转化生长因子-β(1)刺激的TECs通过牛TBM制剂的迁移能力。总之，这些结果表明，基底膜的结构、完整性和组成在决定间质对TECs的影响以及随后对潜在的异常细胞-基质相互作用的影响中发挥着重要作用。
During progression of chronic renal disease, qualitative and quantitative changes in the composition of tubular basement membranes (TBMs) and interstitial matrix occur. Transforming growth factor (TGF)-beta(1)-mediated activation of tubular epithelial cells (TECs) is speculated to be a key contributor to the progression of tubulointerstitial fibrosis. To further understand the pathogenesis associated with renal fibrosis, we developed an in vitro Boyden chamber system using renal basement membranes that partially mimics in vivo conditions of TECs during health and disease. Direct stimulation of TECs with TGF-beta(1)-epithelial growth factor results in an increased migratory capacity across bovine TBM preparations. This is associated with increased matrix metalloproteinase (MMP) production, namely MMP-2 and MMP-9. Indirect chemotactic stimulation by TGF-beta(1)-EGF or collagen type I was insufficient in inducing migration of untreated TECs across bovine TBM preparation, suggesting that basement membrane integrity and composition play an important role in protecting TECs from interstitial fibrotic stimuli. Additionally, neutralization of MMPs by COL-3 inhibitor dramatically decreases the capacity of TGF-beta(1)-stimulated TECs to migrate through bovine TBM preparation. Collectively, these results demonstrate that basement membrane structure, integrity, and composition play an important role in determining interstitial influences on TECs and subsequent impact on potential aberrant cell-matrix interactions.