The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz

• Published in: The Journal of biological chemistry Vol. 293; no. 50; pp. 19290 - 19302
• Main Authors: Feng, Ye, Liang, Yan, Zhu, Xingwen, Wang, Mingjie, Gui, Yuan, Lu, Qingmiao, Gu, Mengru, Xue, Xian, Sun, Xiaoli, He, Weichun, Yang, Junwei, Johnson, Randy L., Dai, Chunsun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-12-2018; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Cycle Proteins; cell signaling; Down-Regulation; Fibrosis; Hippo pathway; kidney; Kidney - pathology; macrophage; macrophage polarization; Macrophages - cytology; Male; Mice; Mice, Inbred C57BL; Phosphoproteins - metabolism; Signal Transduction; Trans-Activators; Transcription Factors - metabolism; Transcription, Genetic; transforming growth factor; Transforming Growth Factor beta1 - metabolism; Wnt signaling; Wnt-5a Protein - metabolism; Wnt5a; Yap/Taz; kidney; Wnt signaling; Hippo pathway; Wnt5a; cell signaling; Yap/Taz; macrophage; macrophage polarization; fibrosis; transforming growth factor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.005457

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 β1 (TGFβ1)-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 TGFβ1-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.