BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury
BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury
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DOI：
10.1038/nm888
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发表时间：
2003-07-01
期刊：
影响因子：
82.9
通讯作者：
Kalluri, R
中科院分区：
文献类型：
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作者：
Zeisberg, M;Hanai, J;Kalluri, R
骨形态发生蛋白（Bone morphogenic protein， BMP）-7是一种35 kda的二聚体蛋白，是转化生长因子(TGF)- β超家族的成员(1)。BMP-7在肾脏中表达最高，其基因缺失会导致小鼠眼睛、骨骼和肾脏发育严重受损(2)。在这里，我们报道BMP-7通过再诱导E-cadherin（一种关键的上皮细胞粘附分子）逆转tgf - β 1诱导的上皮到间质转化（EMT）(3)。此外，我们提供了smad依赖性逆转tgf - β 1诱导的肾小管上皮细胞和乳腺导管上皮细胞中BMP-7的分子证据。在肾脏中，emt诱导的肌成纤维细胞积聚和随后的小管萎缩被认为是慢性肾损伤期间肾纤维化的关键决定因素。因此，我们在慢性肾损伤小鼠模型中测试了BMP-7逆转tgf - β 1诱导的新生EMT的潜力(4)。我们的研究结果表明，全身给药重组人BMP-7可以修复严重受损的肾小管上皮细胞，并与慢性肾损伤的逆转有关。总的来说，这些结果提供了BMP-7和tgf - β之间的串扰在健康和疾病中调节EMT的证据。
Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily(1). BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development(2). Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule(3). Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury(4). Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.