The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz
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 Wn...
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| Veröffentlicht in: | The Journal of biological chemistry 2018-12, Vol.293 (50), p.19290-19302 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1074/jbc.RA118.005457 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.RA118.005457</identifier><identifier>PMID: 30333225</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>The Journal of biological chemistry, 2018-12, Vol.293 (50), p.19290-19302</ispartof><rights>2018 © 2018 Feng et al.</rights><rights>2018 Feng et al.</rights><rights>2018 Feng et al. 2018 Feng et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4057-383298d71d7f89a8749ffc38a403d0eac83373c2e7499849bcd75fc9792db3443</citedby><cites>FETCH-LOGICAL-c4057-383298d71d7f89a8749ffc38a403d0eac83373c2e7499849bcd75fc9792db3443</cites><orcidid>0000-0001-7616-2469</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302175/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302175/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27902,27903,53768,53770</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30333225$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Feng, Ye</creatorcontrib><creatorcontrib>Liang, Yan</creatorcontrib><creatorcontrib>Zhu, Xingwen</creatorcontrib><creatorcontrib>Wang, Mingjie</creatorcontrib><creatorcontrib>Gui, Yuan</creatorcontrib><creatorcontrib>Lu, Qingmiao</creatorcontrib><creatorcontrib>Gu, Mengru</creatorcontrib><creatorcontrib>Xue, Xian</creatorcontrib><creatorcontrib>Sun, Xiaoli</creatorcontrib><creatorcontrib>He, Weichun</creatorcontrib><creatorcontrib>Yang, Junwei</creatorcontrib><creatorcontrib>Johnson, Randy L.</creatorcontrib><creatorcontrib>Dai, Chunsun</creatorcontrib><title>The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Cell Cycle Proteins</subject><subject>cell signaling</subject><subject>Down-Regulation</subject><subject>Fibrosis</subject><subject>Hippo pathway</subject><subject>kidney</subject><subject>Kidney - pathology</subject><subject>macrophage</subject><subject>macrophage polarization</subject><subject>Macrophages - cytology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Phosphoproteins - metabolism</subject><subject>Signal Transduction</subject><subject>Trans-Activators</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><subject>transforming growth factor</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Wnt signaling</subject><subject>Wnt-5a Protein - metabolism</subject><subject>Wnt5a</subject><subject>Yap/Taz</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1UcFu1DAQtRCILoU7J-Qjl2ztOMEOB6SqagtSJSS0CDhZE3uSdcnawU4qbX-DP-FD-CYctlRwwBdrNO-9mXmPkOecrTmT1cl1a9YfTjlXa8bqqpYPyIozJQpR888PyYqxkhdNWasj8iSla5Zf1fDH5EgwIURZ1ivyfbNFmlzvYXC-p2MMEzpPP_mphqXa5TrRzeXFzx-82KF1MKGlOzAxjFvokY5hgOhuYXLBU_CWfnXW4552ro0huUTbPXXezmaRn_KwKYJPJrpxYcBAI_bzAFOIiX6B8WQDt0_Jow6GhM_u_mPy8eJ8c_a2uHp_-e7s9KowFatlIZQoG2Ult7JTDShZNV1nhIKKCcsQjBJCClNibjSqalpjZd2ZRjalbUVViWPy5qA7zm0-zaDPuw16jG4Hca8DOP1vx7ut7sONfiWysbLOAi_vBGL4NmOa9M4lg8MAHsOcdMmzx0oxsUDZAZqNSylidz-GM71kqXOW-neW-pBlprz4e717wp_wMuD1AYDZpBuHUSfj0JucUkQzaRvc_9V_Abk2svk</recordid><startdate>20181214</startdate><enddate>20181214</enddate><creator>Feng, Ye</creator><creator>Liang, Yan</creator><creator>Zhu, Xingwen</creator><creator>Wang, Mingjie</creator><creator>Gui, Yuan</creator><creator>Lu, Qingmiao</creator><creator>Gu, Mengru</creator><creator>Xue, Xian</creator><creator>Sun, Xiaoli</creator><creator>He, Weichun</creator><creator>Yang, Junwei</creator><creator>Johnson, Randy L.</creator><creator>Dai, Chunsun</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7616-2469</orcidid></search><sort><creationdate>20181214</creationdate><title>The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4057-383298d71d7f89a8749ffc38a403d0eac83373c2e7499849bcd75fc9792db3443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Cell Cycle Proteins</topic><topic>cell signaling</topic><topic>Down-Regulation</topic><topic>Fibrosis</topic><topic>Hippo pathway</topic><topic>kidney</topic><topic>Kidney - pathology</topic><topic>macrophage</topic><topic>macrophage polarization</topic><topic>Macrophages - cytology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Phosphoproteins - metabolism</topic><topic>Signal Transduction</topic><topic>Trans-Activators</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic</topic><topic>transforming growth factor</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Wnt signaling</topic><topic>Wnt-5a Protein - metabolism</topic><topic>Wnt5a</topic><topic>Yap/Taz</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Feng, Ye</creatorcontrib><creatorcontrib>Liang, Yan</creatorcontrib><creatorcontrib>Zhu, Xingwen</creatorcontrib><creatorcontrib>Wang, Mingjie</creatorcontrib><creatorcontrib>Gui, Yuan</creatorcontrib><creatorcontrib>Lu, Qingmiao</creatorcontrib><creatorcontrib>Gu, Mengru</creatorcontrib><creatorcontrib>Xue, Xian</creatorcontrib><creatorcontrib>Sun, Xiaoli</creatorcontrib><creatorcontrib>He, Weichun</creatorcontrib><creatorcontrib>Yang, Junwei</creatorcontrib><creatorcontrib>Johnson, Randy L.</creatorcontrib><creatorcontrib>Dai, Chunsun</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Feng, Ye</au><au>Liang, Yan</au><au>Zhu, Xingwen</au><au>Wang, Mingjie</au><au>Gui, Yuan</au><au>Lu, Qingmiao</au><au>Gu, Mengru</au><au>Xue, Xian</au><au>Sun, Xiaoli</au><au>He, Weichun</au><au>Yang, Junwei</au><au>Johnson, Randy L.</au><au>Dai, Chunsun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2018-12-14</date><risdate>2018</risdate><volume>293</volume><issue>50</issue><spage>19290</spage><epage>19302</epage><pages>19290-19302</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30333225</pmid><doi>10.1074/jbc.RA118.005457</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-7616-2469</orcidid><oa>free_for_read</oa></addata></record> |
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| 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 |
| title | The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz |
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