Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis
Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis
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DOI：
10.1016/s0002-9440(10)62533-3
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发表时间：
2001-10-01
影响因子：
6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Yang, JW;Liu, YH
肌成纤维细胞的激活在慢性肾脏疾病的进展中起着关键作用。新的证据表明，肌成纤维细胞可以通过上皮细胞向间充质细胞的转化(EMT)从肾小管上皮细胞分化为肌成纤维细胞；然而，关于这两种细胞之间转化的细节尚不清楚。在这里，我们剖析了转化生长因子-β1诱导EMT过程中的关键事件。人肾小管上皮细胞与转化生长因子-β1孵育后，α-平滑肌肌动蛋白从头开始表达，上皮性标志物E-钙粘附素丢失，肌成纤维细胞形态转化，间质基质产生。时程研究表明，E-钙粘附素的丢失是EMT中其他改变之前的早期事件。转化的细胞分泌大量的基质金属蛋白酶-2，特异性降解肾小管基底膜。它们还表现出更强的运动性和侵袭能力。在单侧输尿管梗阻引起的小鼠肾纤维化模型中，这些体外培养上皮细胞表型的改变基本上被概括。因此，这些结果表明，肾小管上皮细胞向肌成纤维细胞的转变是一个有组织的、高度调控的过程，包括四个关键步骤：1)上皮细胞的丢失。细胞黏附，2)α-平滑肌肌动蛋白表达和肌动蛋白重组，3)肾小管基底膜破坏，4)细胞迁移和侵袭增强。
Myofibroblast activation is a key event playing a critical role in the progression of chronic renal disease. Emerging evidence suggests that myofibroblasts can derive from tubular epithelial cells by an epithelial to mesenchymal transition (EMT); however, the details regarding the conversion between these two cell types are poorly understood. Here we dissect the key events during the process of EMT induced by transforming growth factor-beta1. incubation of human tubular epithelial cells with transforming growth factor-beta1 induced de novo expression of alpha -smooth muscle actin, loss of epithelial marker E-cadherin, transformation of myofibroblastic morphology, and production of interstitial matrix. Time-course studies revealed that loss of E-cadherin was an early event that preceded other alterations during EMT. The transformed cells secreted a large amount of matrix metalloproteinase-2 that specifically degraded tubular basement membrane. They also exhibited an enhanced motility and invasive capacity. These alterations in epithelial phenotypes in vitro were essentially recapitulated in a mouse model of renal fibrosis induced by unilateral ureteral obstruction. Hence, these results indicate that tubular epithelial to myofibroblast transition is an orchestrated, highly regulated process involving four key steps including: 1) loss of epithelial. cell adhesion, 2) de novo alpha -smooth muscle actin expression and actin reorganization, 3) disruption of tubular basement membrane, and 4) enhanced cell migration and invasion.