The signaling protein Wnt5a promotes TGF1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz

被引:104
作者
Feng, Ye [1 ]
Liang, Yan [1 ]
Zhu, Xingwen [1 ]
Wang, Mingjie [1 ]
Gui, Yuan [1 ]
Lu, Qingmiao [1 ]
Gu, Mengru [1 ]
Xue, Xian [1 ]
Sun, Xiaoli [1 ]
He, Weichun [1 ]
Yang, Junwei [1 ]
Johnson, Randy L. [2 ]
Dai, Chunsun [1 ]
机构
[1] Nanjing Med Univ, Affiliated Hosp 2, Ctr Kidney Dis, 262 North Zhongshan Rd, Nanjing 210003, Jiangsu, Peoples R China
[2] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
基金
美国国家科学基金会;
关键词
kidney; fibrosis; Wnt signaling; Hippo pathway; macrophage; cell signaling; macrophage polarization; transforming growth factor; Wnt5a; Yap; Taz; FIBROBLAST ACTIVATION; HIPPO PATHWAY; TAZ; YAP; CANCER; CONTRIBUTES; TARGET; INJURY; CELLS; STAT6;
D O I
10.1074/jbc.RA118.005457
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:19290 / 19302
页数:13
相关论文
共 44 条
[1]   Wnt5a is elevated in heart failure and affects cardiac fibroblast function [J].
Abraityte, Aurelija ;
Vinge, Leif E. ;
Askevold, Erik T. ;
Lekva, Tove ;
Michelsen, Annika E. ;
Ranheim, Trine ;
Alfsnes, Katrine ;
Fiane, Arnt ;
Aakhus, Svend ;
Lunde, Ida G. ;
Dahl, Christen P. ;
Aukrust, Pal ;
Christensen, Geir ;
Gullestad, Lars ;
Yndestad, Arne ;
Ueland, Thor .
JOURNAL OF MOLECULAR MEDICINE-JMM, 2017, 95 (07) :767-777
[2]   Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype [J].
Anorga, Sandybell ;
Overstreet, Jessica M. ;
Falke, Lucas L. ;
Tang, Jiaqi ;
Goldschmeding, Roel G. ;
Higgins, Paul J. ;
Samarakoon, Rohan .
FASEB JOURNAL, 2018, 32 (05) :2644-2657
[3]   Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients [J].
Bergenfelz, Caroline ;
Medrek, Catharina ;
Ekstrom, Elin ;
Jirstrom, Karin ;
Janols, Helena ;
Wullt, Marlene ;
Bredberg, Anders ;
Leandersson, Karin .
JOURNAL OF IMMUNOLOGY, 2012, 188 (11) :5448-5458
[4]   Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations [J].
Clements, Meghan ;
Gershenovich, Michael ;
Chaber, Christopher ;
Campos-Rivera, Juanita ;
Du, Pan ;
Zhang, Mindy ;
Ledbetter, Steve ;
Zuk, Anna .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2016, 27 (01) :159-170
[5]   Wnt/β-Catenin Signaling and Disease [J].
Clevers, Hans ;
Nusse, Roel .
CELL, 2012, 149 (06) :1192-1205
[6]   Wnt/β-Catenin Signaling Promotes Podocyte Dysfunction and Albuminuria [J].
Dai, Chunsun ;
Stolz, Donna B. ;
Kiss, Lawrence P. ;
Monga, Satdarshan P. ;
Holzman, Lawrence B. ;
Liu, Youhua .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2009, 20 (09) :1997-2008
[7]   Wnt/β-Catenin-Promoted Macrophage Alternative Activation Contributes to Kidney Fibrosis [J].
Feng, Ye ;
Ren, Jiafa ;
Gui, Yuan ;
Wei, Wei ;
Shu, Bingyan ;
Lu, Qingmiao ;
Xue, Xian ;
Sun, Xiaoli ;
He, Weichun ;
Yang, Junwei ;
Dai, Chunsun .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2018, 29 (01) :182-193
[8]   The Hippo pathway in organ development, homeostasis, and regeneration [J].
Fu, Vivian ;
Plouffe, Steven W. ;
Guan, Kun-Liang .
CURRENT OPINION IN CELL BIOLOGY, 2017, 49 :99-107
[9]   Wnt Regulation of Planar Cell Polarity (PCP) [J].
Gao, Bo .
PLANAR CELL POLARITY DURING DEVELOPMENT, 2012, 101 :263-295
[10]   The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells [J].
Geng, Jing ;
Yu, Shujuan ;
Zhao, Hao ;
Sun, Xiufeng ;
Li, Xun ;
Wang, Ping ;
Xiong, Xiaolin ;
Hong, Lixin ;
Xie, Changchuan ;
Gao, Jiahui ;
Shi, Yiran ;
Peng, Jiaqi ;
Johnson, Randy L. ;
Xiao, Nengming ;
Lu, Linrong ;
Han, Jiahuai ;
Zhou, Dawang ;
Chen, Lanfen .
NATURE IMMUNOLOGY, 2017, 18 (07) :800-+