Bone Morphogenetic Protein-7 Inhibits Proximal Tubular Epithelial Cell Smad3 Signaling via Increased SnoN Expression
Bone Morphogenetic Protein-7 Inhibits Proximal Tubular Epithelial Cell Smad3 Signaling via Increased SnoN Expression
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DOI：
10.2353/ajpath.2010.090459
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Fraser, Donald
中科院分区：
文献类型：
--
作者：
Luo, Dong Dong;Phillips, Aled;Fraser, Donald
骨形态发生蛋白-7（BMP-7）通过对抗转化生长因子β 1（TGF-β）依赖性纤维化改善纤维化肾病动物模型的结局。然而，潜在的机制仍然不清楚。在这里，我们研究了BMP-7对近端肾小管细胞系HK-2（PTC）中TGF-β反应的影响。BMP-7特异性地限制Smad 3而不是Smad 2信号传导。BMP-7不抑制Smad 3磷酸化或核积累，也不改变磷酸化的Smad 3去磷酸化或降解。然而，BMP-7处理减少了Smad 3 DNA与共有Smad结合元件探针的结合，染色质免疫沉淀显示，与单独的TGF-β相比，BMP-7和TGF-β处理的PTC中Smad 3与纤溶酶原激活物抑制剂-1启动子的结合减少。转录抑制因子SnoN的降解最近被证明是Smad 3（而不是Smad 2）信号传导所必需的。TGF-β刺激后，PTC中SnoN表达短暂丧失，但BMP-7阻止了这一点。此外，BMP-7在siRNA介导的SnoN敲低后对Smad 3信号传导没有影响，而用蛋白酶体抑制剂MG 132预防SnoN降解再现了BMP-7对Smad 3信号传导的抑制作用。我们的结论是，BMP-7防止TGF-β介导的转录抑制因子SnoN的损失，因此特别限制Smad 3 DNA结合，改变PTCs中TGF-β的转录反应的平衡。这些结果为TGF-β信号传导的关键调节因子提供了重要的机制见解。(Am J Pathol 2010，176：1139-1147; DOI：10.2353/ajpath.2010.090459）
Bone morphogenetic protein-7 (BMP-7) improves outcome in animal models of fibrotic renal disease by opposing transforming growth factor beta 1 (TGF-beta)-dependent fibrosis. However, the underlying mechanisms remain obscure. Here, we studied the effect of BMP-7 on response to TGF-beta in the proximal tubular cell line HK-2 (PTC). BMP-7 specifically limited Smad3 but not Smad2 signaling. BMP-7 did not inhibit Smad3 phosphorylation or nuclear accumulation, nor did BMP-7 alter phosphorylated Smad3 dephosphorylation or degradation. However, BMP-7 treatment reduced Smad3 DNA binding to a consensus Smad binding element probe, and chromatin immunoprecipitation showed reduced Smad3 binding to the plasminogen activator inhibitor-1 promoter in PTCs treated with BMP-7 and TGF-beta compared with TGF-beta alone. Degradation of the transcriptional repressor SnoN has recently been shown to be necessary for Smad3 (but not Smad2) signaling. SnoN expression was transiently lost in PTCs after TGF-beta stimulation, but BMP-7 prevented this. Furthermore, BMP-7 had no effect on Smad3 signaling after siRNA-mediated SnoN knockdown, whereas prevention of SnoN degradation with the proteasome inhibitor MG132 reproduced the inhibitory action of BMP-7 on Smad3 signaling. We conclude that BMP-7 prevents TGF-beta-mediated loss of the transcriptional repressor SnoN and hence specifically limits Smad3 DNA binding, altering the balance of transcriptional responses to TGF-beta in PTCs. These results provide an important mechanistic insight into a key regulator of TGF-beta signaling. (Am J Pathol 2010, 176:1139-1147; DOI: 10.2353/ajpath.2010.090459)