Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria
Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria
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DOI：
10.2353/ajpath.2008.070057
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发表时间：
2008-02-01
影响因子：
6
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
--
作者：
Li, Yingjian;Kang, Young Sun;Liu, Youhua
足细胞功能障碍在蛋白尿和肾小球硬化的发病机制中起着重要作用。然而，许多常见慢性肾脏疾病中足细胞功能障碍的机制仍知之甚少。在这里，我们测试了足细胞在损伤后可能经历上皮间质转化的假设。将条件永生化的小鼠足细胞与转化生长因子 (TGF)-β1 一起孵育，转化生长因子 -β1 是一种强效纤维形成细胞因子，在患病肾脏中上调。 TGF-β1抑制裂隙隔膜相关蛋白P-钙粘蛋白、闭锁小带-1和去氧肾上腺素，这一变化与上皮特征的丧失一致。同时，TGF-β1诱导中间丝蛋白结蛋白、间质基质成分纤连蛋白和I型胶原的表达。此外，TGF-β1促进足细胞表达和分泌基质金属蛋白酶9。从功能上讲，TGF-β1 增加了白蛋白跨足细胞单层的通透性，如细胞旁白蛋白流入测定所证明的。 Snail 是启动上皮间质转化的关键转录因子，由 TGF-β 1 诱导，Snail 的异位表达抑制足细胞中的 P-钙粘蛋白和去氧肾上腺素。在体内，除了去氧肾上腺素和闭锁小带-1的丢失外，在肾小球足细胞中还可以观察到间充质标记物，例如结蛋白、成纤维细胞特异性蛋白-1和基质金属蛋白酶-9；糖尿病肾病。这些结果表明足细胞去分化和间质转化可能是导致足细胞功能障碍的潜在途径，从而在蛋白尿的发生中发挥作用。
Podocyte dysfunction plays an essential role in the pathogenesis of proteinuria and glomerulosclerosis. However, the mechanism underlying podocyte dysfunction in many common forms of chronic kidney diseases remains poorly understood. Here we tested the hypothesis that podocytes may undergo epithelial-to-mesenchymal transition after injury. Conditionally immortalized mouse podocytes were incubated with transforming growth factor (TGF)-beta 1, a potent fibrogenic cytokine that is up-regulated in the diseased kidney. TGF-beta 1 suppressed the slit diaphragm-associated protein P-cadherin, zonula occludens-1, and nephrin, a change consistent with loss of the epithelial feature. Meanwhile, TGF-beta 1 induced the expression of the intermediate filament protein desmin and interstitial matrix components fibronectin and collagen I. Furthermore, TGF-beta 1 promoted the expression and secretion of matrix metalloproteinase-9 by podocytes. Functionally, TGF-beta 1 increased albumin permeability across podocyte monolayers, as demonstrated by a paracellular albumin influx assay. The expression of Snail, a key transcriptional factor that has been implicated in initiating epithelial-to-mesenchymal transition, was induced by TGF-beta 1, and ectopic expression of Snail suppressed P-cadherin and nephrin in podocytes. In vivo, in addition to loss of nephrin and zonula occludens-1, mesenchymal markers such as desmin, fibroblast-specific protein-1, and matrix metalloproteinase-9 could be observed in glomerular podocytes; of diabetic nephropathy. These results suggest that podocyte dedifferentiation and mesenchymal transition could be a potential pathway leading to their dysfunction, thereby playing a role in the genesis of proteinuria.