Tubular Overexpression of Transforming Growth Factor-β1 Induces Autophagy and Fibrosis but Not Mesenchymal Transition of Renal Epithelial Cells
Tubular Overexpression of Transforming Growth Factor-β1 Induces Autophagy and Fibrosis but Not Mesenchymal Transition of Renal Epithelial Cells
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DOI：
10.2353/ajpath.2010.091012
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发表时间：
2010-08-01
影响因子：
6
通讯作者：
Kriz, Wilhelm
中科院分区：
文献类型：
--
作者：
Koesters, Robert;Kaissling, Brigitte;Kriz, Wilhelm
我们最近在四环素控制的转基因小鼠模型中发现，肾小管中转化生长因子（TGF）-β1的过度表达会诱导广泛的肾小管周围纤维化和肾单位局灶性变性。在本研究中，我们分析了这些现象背后的机制。对肾小管细胞衍生的 TGF-β1 的最初反应包括肾小管周围细胞的强劲增殖和胶原蛋白的沉积。在持续表达时，肾单位以局灶性模式退化。这个过程从肾小管去分化开始，然后通过自噬进行肾小管细胞的完全分解。最终结果是空的塌陷的管状基底膜残余物嵌入致密的胶原纤维组织中。相应的肾小球作为管状残余物存活下来。因此，TGF-β1驱动的自噬可能代表了一种新的肾小管分解机制。在完整肾小管之间和肾小管分解区域中看到的纤维化是由源自局部成纤维细胞的肌成纤维细胞引起的。没有发现肾小管细胞转变为肌成纤维细胞的证据。电子显微照片中受损肾小管的追踪和肾小管上皮细胞的基因标记均未显示细胞侵入肾小管基底膜。总之，体内肾小管中 TGF-β1 的过度表达会诱导间质增殖、肾小管自噬和纤维化，但不会诱导上皮间质转化。 （Am J Pat 2010，177：632-643；DOI：10.2353/ajpath.2010.091012）
We recently showed in a tetracycline-controlled transgenic mouse model that overexpression of transforming growth factor (TGF)-beta 1 in renal tubules induces widespread peritubular fibrosis and focal degeneration of nephrons. In the present study we have analyzed the mechanisms underlying these phenomena. The initial response to tubular cell-derived TGF-beta 1 consisted of a robust proliferation of peritubular cells and deposition of collagen. On sustained expression, nephrons degenerated in a focal pattern. This process started with tubular dedifferentiation and proceeded to total decomposition of tubular cells by autophagy. The final outcome was empty collapsed remnants of tubular basement membrane embedded into a dense collagenous fibrous tissue. The corresponding glomeruli survived as atubular remnants. Thus, TGF-beta 1 driven autophagy may represent a novel mechanism of tubular decomposition. The fibrosis seen in between intact tubules and in areas of tubular decomposition resulted from myofibroblasts that were derived from local fibroblasts. No evidence was found for a transition of tubular cells into myofibroblasts. Neither tracing of injured tubules in electron micrographs nor genetic tagging of tubular epithelial cells revealed cells transgressing the tubular basement membrane. In conclusion, overexpression of TGF-beta 1 in renal tubules in vivo induces interstitial proliferation, tubular autophagy, and fibrosis, but not epithelial-to-mesenchymal transition. (Am J Pat 2010, 177:632-643; DOI: 10.2353/ajpath.2010.091012)