Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney
Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney
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DOI：
10.1074/jbc.m413102200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Zeisberg, M;Shah, AA;Kalluri, R
在肾脏中，上皮间充质细胞之间存在独特的可塑性。在肾脏发育过程中，后肾间充质通过间充质向上皮转化（MET）促进肾单位上皮的形成。在受损的成年肾脏中，肾上皮细胞通过上皮-间质转化促进成纤维细胞的产生，从而促进肾纤维化。重组人骨形态发生蛋白（BMP）-7是一种在肾脏发育过程中从致密间充质转化为上皮细胞所必需的形态原，可增强肾脏中管状结构的修复。在这种情况下，BMP-7抑制涉及成人肾小管上皮细胞的上皮-间充质转化，并减少成人肾成纤维细胞分泌I型胶原。为了寻找BMP-7修复受损肾小管能力的机制，我们假设用BMP-7全身治疗可能诱导MET，涉及受损肾脏中的成人肾成纤维细胞，产生功能性上皮细胞。在这里，我们报告说，BMP-7诱导形成上皮细胞聚集体在成人肾成纤维细胞与重新获得的E-钙粘蛋白表达和运动性下降，模仿BMP-7对胚胎后肾间充质产生上皮细胞的影响。此外，我们提供的证据表明，BMP-7介导的肾损伤修复与MET相关，涉及肾纤维化小鼠模型中的成人肾间质成纤维细胞。总的来说，这些发现表明，成年肾成纤维细胞可能保留其原始胚胎印记和可塑性的一部分，这可以通过全身施用BMP-7来重新参与，以介导纤维化肾脏中肾小管损伤的修复。
In the kidney, a unique plasticity exists between epithelial mesenchymal cells. During kidney development, the metanephric mesenchyme contributes to emerging epithelium of the nephron via mesenchymal to epithelial transition ( MET). In the injured adult kidney, renal epithelia contribute to the generation of fibroblasts via epithelial-mesenchymal transition, facilitating renal fibrosis. Recombinant human bone morphogenic protein ( BMP)-7, a morphogen that is essential for the conversion of epithelia from condensing mesenchyme during kidney development, enhances the repair of tubular structures in the kidney. In this setting, BMP-7 inhibits epithelial-mesenchymal transition involving adult renal epithelial tubular cells and decreases secretion of type I collagen by adult renal fibroblasts. In search of a mechanism behind the ability of BMP-7 to repair damaged renal tubules, we hypothesized that systemic treatment with BMP-7 might induce MET involving adult renal fibroblasts in the injured kidney, generating functional epithelial cells. Here we report that BMP-7 induces formation of epithelial cell aggregates in adult renal fibroblasts associated with reacquisition of E-cadherin expression and decreased motility, mimicking the effect of BMP-7 on embryonic metanephric mesenchyme to generate epithelium. In addition, we provide evidence that BMP-7-mediated repair of renal injury is associated with MET involving adult renal interstitial fibroblasts in mouse models for renal fibrosis. Collectively, these findings suggest that adult renal fibroblasts might retain parts of their original embryonic imprint and plasticity, which can be re-engaged by systemic administration of BMP-7 to mediate repair of tubular injury in a fibrotic kidney.