The signaling protein Wnt5a promotes TGF1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz
The signaling protein Wnt5a promotes TGF1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz
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DOI：
10.1074/jbc.ra118.005457
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发表时间：
2018-12-14
影响因子：
4.8
通讯作者：
Dai, Chunsun
中科院分区：
文献类型：
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作者：
Feng, Ye;Liang, Yan;Dai, Chunsun
已知M2巨噬细胞极化是肾纤维化的基础。我们先前报道了Wnt家族的大多数成员在纤维化肾脏中被诱导。信号蛋白Wnt 5a的失调与纤维化相关，但关于Wnt 5a在调节导致肾纤维化的M2巨噬细胞活化中的作用知之甚少。在这里，使用小鼠Raw 264.7细胞和骨髓来源的巨噬细胞，我们发现Wnt 5a增强转化生长因子1（TGF 1）诱导的巨噬细胞M2极化以及转录调节因子Yes相关蛋白（雅普）/具有PDZ结合基序（Taz）的转录辅激活因子的表达。维替泊芬阻断雅普/Taz抑制Wnt 5a和TGF 1诱导的巨噬细胞M2极化。在肾纤维化小鼠模型中，shRNA介导的Wnt 5a表达的敲低减少了肾纤维化、巨噬细胞雅普/Taz表达和M2极化。此外，巨噬细胞中Taz的基因消融减弱了小鼠的肾纤维化和巨噬细胞M2极化。总的来说，这些结果表明Wnt 5a通过刺激雅普/Taz介导的巨噬细胞M2极化促进肾纤维化。
M2 macrophage polarization is known to underlie kidney fibrosis. We previously reported that most of the members of the Wnt family of signaling proteins are induced in fibrotic kidneys. Dysregulation of the signaling protein Wnt5a is associated with fibrosis, but little is known about the role of Wnt5a in regulating M2 macrophage activation that results in kidney fibrosis. Here, using murine Raw 264.7 cells and bone marrow-derived macrophages, we found that Wnt5a enhanced transforming growth factor 1 (TGF1)-induced macrophage M2 polarization as well as expression of the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz). Verteporfin blockade of Yap/Taz inhibited both Wnt5a- and TGF1-induced macrophage M2 polarization. In mouse models of kidney fibrosis, shRNA-mediated knockdown of Wnt5a expression diminished kidney fibrosis, macrophage Yap/Taz expression, and M2 polarization. Moreover, genetic ablation of Taz in macrophages attenuated kidney fibrosis and macrophage M2 polarization in mice. Collectively, these results indicate that Wnt5a promotes kidney fibrosis by stimulating Yap/Taz-mediated macrophage M2 polarization.