CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis
Recent studies have shown that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying the recruitment of bone marrow-derived fibroblasts into the kidney are incompletely understood. Bone marrow-derived fibroblasts...
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| description | Recent studies have shown that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying the recruitment of bone marrow-derived fibroblasts into the kidney are incompletely understood. Bone marrow-derived fibroblasts express the chemokine receptor--CCR2. In this study, we tested the hypothesis that CCR2 participates in the recruitment of fibroblasts into the kidney during the development of renal fibrosis. Bone marrow-derived collagen-expressing GFP⁺ fibroblasts were detected in the obstructed kidneys of chimeric mice transplanted with donor bone marrow from collagen α1(I)-GFP reporter mice. These bone marrow-derived fibroblasts expressed PDGFR-β and CCR2. CCR2 knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors expressing the hematopoietic marker-CD45 and the mesenchymal markers-PDGFR-β or procollagen I in the obstructed kidneys compared with wild-type mice. Furthermore, CCR2 knockout mice displayed fewer bone marrow-derived myofibroblasts and expressed less α-SMA or FSP-1 in the obstructed kidneys compared with wild-type mice. Consistent with these findings, genetic deletion of CCR2 inhibited total collagen deposition and suppressed expression of collagen I and fibronectin. Moreover, genetic deletion of CCR2 inhibits MCP-1 and CXCL16 gene expression associated with a reduction of inflammatory cytokine expression and macrophage infiltration, suggesting a linear interaction between two chemokines/ligand receptors in tubular epithelial cells. Taken together, our results demonstrate that CCR2 signaling plays an important role in the pathogenesis of renal fibrosis through regulation of bone marrow-derived fibroblasts. These data suggest that inhibition of CCR2 signaling could constitute a novel therapeutic approach for fibrotic kidney disease. |
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However, the molecular mechanisms underlying the recruitment of bone marrow-derived fibroblasts into the kidney are incompletely understood. Bone marrow-derived fibroblasts express the chemokine receptor--CCR2. In this study, we tested the hypothesis that CCR2 participates in the recruitment of fibroblasts into the kidney during the development of renal fibrosis. Bone marrow-derived collagen-expressing GFP⁺ fibroblasts were detected in the obstructed kidneys of chimeric mice transplanted with donor bone marrow from collagen α1(I)-GFP reporter mice. These bone marrow-derived fibroblasts expressed PDGFR-β and CCR2. CCR2 knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors expressing the hematopoietic marker-CD45 and the mesenchymal markers-PDGFR-β or procollagen I in the obstructed kidneys compared with wild-type mice. Furthermore, CCR2 knockout mice displayed fewer bone marrow-derived myofibroblasts and expressed less α-SMA or FSP-1 in the obstructed kidneys compared with wild-type mice. Consistent with these findings, genetic deletion of CCR2 inhibited total collagen deposition and suppressed expression of collagen I and fibronectin. Moreover, genetic deletion of CCR2 inhibits MCP-1 and CXCL16 gene expression associated with a reduction of inflammatory cytokine expression and macrophage infiltration, suggesting a linear interaction between two chemokines/ligand receptors in tubular epithelial cells. Taken together, our results demonstrate that CCR2 signaling plays an important role in the pathogenesis of renal fibrosis through regulation of bone marrow-derived fibroblasts. These data suggest that inhibition of CCR2 signaling could constitute a novel therapeutic approach for fibrotic kidney disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0077493</identifier><identifier>PMID: 24130892</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antigens ; Bone marrow ; Bone Marrow - pathology ; Bone marrow transplantation ; CC chemokine receptors ; CCR2 protein ; CD45 antigen ; Cell Line ; Chemokine CCL2 - genetics ; Chemokine CXCL16 ; Chemokine CXCL6 - genetics ; Chemokines ; Clonal deletion ; Collagen ; Collagen (type I) ; Collagen Type I - analysis ; CXCL16 protein ; Digital cameras ; Epithelial cells ; Fibroblasts ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Fibronectin ; Fibronectins ; Fibrosis ; Gene Deletion ; Gene expression ; Gene Expression Regulation ; Genes ; Hemopoiesis ; Immunoglobulins ; Infiltration ; Inflammation ; Kidney - metabolism ; Kidney - pathology ; Kidney diseases ; Kidney Diseases - genetics ; Kidney Diseases - pathology ; Kidney transplantation ; Kidneys ; Laboratory animals ; Macrophages ; Medicine ; Mesenchyme ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular chains ; Molecular modelling ; Monocyte chemoattractant protein 1 ; Morphology ; Myofibroblasts - metabolism ; Myofibroblasts - pathology ; Nephrology ; Osteoprogenitor cells ; Pathogenesis ; Platelet-derived growth factor ; Procollagen ; Proteins ; Quantitative analysis ; Receptors ; Receptors, CCR2 - genetics ; Rodents ; Signaling</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e77493</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Xia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Xia et al 2013 Xia et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-8620dfda13e38c1dae2e2b7501bb69a5eab9d49ac912e8719c8adecc603828c83</citedby><cites>FETCH-LOGICAL-c758t-8620dfda13e38c1dae2e2b7501bb69a5eab9d49ac912e8719c8adecc603828c83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795063/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795063/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24130892$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xia, Yunfeng</creatorcontrib><creatorcontrib>Entman, Mark L</creatorcontrib><creatorcontrib>Wang, Yanlin</creatorcontrib><title>CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Recent studies have shown that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying the recruitment of bone marrow-derived fibroblasts into the kidney are incompletely understood. Bone marrow-derived fibroblasts express the chemokine receptor--CCR2. In this study, we tested the hypothesis that CCR2 participates in the recruitment of fibroblasts into the kidney during the development of renal fibrosis. Bone marrow-derived collagen-expressing GFP⁺ fibroblasts were detected in the obstructed kidneys of chimeric mice transplanted with donor bone marrow from collagen α1(I)-GFP reporter mice. These bone marrow-derived fibroblasts expressed PDGFR-β and CCR2. CCR2 knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors expressing the hematopoietic marker-CD45 and the mesenchymal markers-PDGFR-β or procollagen I in the obstructed kidneys compared with wild-type mice. Furthermore, CCR2 knockout mice displayed fewer bone marrow-derived myofibroblasts and expressed less α-SMA or FSP-1 in the obstructed kidneys compared with wild-type mice. Consistent with these findings, genetic deletion of CCR2 inhibited total collagen deposition and suppressed expression of collagen I and fibronectin. Moreover, genetic deletion of CCR2 inhibits MCP-1 and CXCL16 gene expression associated with a reduction of inflammatory cytokine expression and macrophage infiltration, suggesting a linear interaction between two chemokines/ligand receptors in tubular epithelial cells. Taken together, our results demonstrate that CCR2 signaling plays an important role in the pathogenesis of renal fibrosis through regulation of bone marrow-derived fibroblasts. These data suggest that inhibition of CCR2 signaling could constitute a novel therapeutic approach for fibrotic kidney disease.</description><subject>Animals</subject><subject>Antigens</subject><subject>Bone marrow</subject><subject>Bone Marrow - pathology</subject><subject>Bone marrow transplantation</subject><subject>CC chemokine receptors</subject><subject>CCR2 protein</subject><subject>CD45 antigen</subject><subject>Cell Line</subject><subject>Chemokine CCL2 - genetics</subject><subject>Chemokine CXCL16</subject><subject>Chemokine CXCL6 - genetics</subject><subject>Chemokines</subject><subject>Clonal deletion</subject><subject>Collagen</subject><subject>Collagen (type I)</subject><subject>Collagen Type I - analysis</subject><subject>CXCL16 protein</subject><subject>Digital cameras</subject><subject>Epithelial cells</subject><subject>Fibroblasts</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - pathology</subject><subject>Fibronectin</subject><subject>Fibronectins</subject><subject>Fibrosis</subject><subject>Gene Deletion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genes</subject><subject>Hemopoiesis</subject><subject>Immunoglobulins</subject><subject>Infiltration</subject><subject>Inflammation</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidney diseases</subject><subject>Kidney Diseases - genetics</subject><subject>Kidney Diseases - pathology</subject><subject>Kidney transplantation</subject><subject>Kidneys</subject><subject>Laboratory animals</subject><subject>Macrophages</subject><subject>Medicine</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Molecular chains</subject><subject>Molecular modelling</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Morphology</subject><subject>Myofibroblasts - metabolism</subject><subject>Myofibroblasts - pathology</subject><subject>Nephrology</subject><subject>Osteoprogenitor cells</subject><subject>Pathogenesis</subject><subject>Platelet-derived growth factor</subject><subject>Procollagen</subject><subject>Proteins</subject><subject>Quantitative analysis</subject><subject>Receptors</subject><subject>Receptors, CCR2 - 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pathology</topic><topic>Bone marrow transplantation</topic><topic>CC chemokine receptors</topic><topic>CCR2 protein</topic><topic>CD45 antigen</topic><topic>Cell Line</topic><topic>Chemokine CCL2 - genetics</topic><topic>Chemokine CXCL16</topic><topic>Chemokine CXCL6 - genetics</topic><topic>Chemokines</topic><topic>Clonal deletion</topic><topic>Collagen</topic><topic>Collagen (type I)</topic><topic>Collagen Type I - analysis</topic><topic>CXCL16 protein</topic><topic>Digital cameras</topic><topic>Epithelial cells</topic><topic>Fibroblasts</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - pathology</topic><topic>Fibronectin</topic><topic>Fibronectins</topic><topic>Fibrosis</topic><topic>Gene Deletion</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genes</topic><topic>Hemopoiesis</topic><topic>Immunoglobulins</topic><topic>Infiltration</topic><topic>Inflammation</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidney diseases</topic><topic>Kidney Diseases - genetics</topic><topic>Kidney Diseases - pathology</topic><topic>Kidney transplantation</topic><topic>Kidneys</topic><topic>Laboratory animals</topic><topic>Macrophages</topic><topic>Medicine</topic><topic>Mesenchyme</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Molecular chains</topic><topic>Molecular modelling</topic><topic>Monocyte chemoattractant protein 1</topic><topic>Morphology</topic><topic>Myofibroblasts - metabolism</topic><topic>Myofibroblasts - pathology</topic><topic>Nephrology</topic><topic>Osteoprogenitor cells</topic><topic>Pathogenesis</topic><topic>Platelet-derived growth factor</topic><topic>Procollagen</topic><topic>Proteins</topic><topic>Quantitative analysis</topic><topic>Receptors</topic><topic>Receptors, CCR2 - genetics</topic><topic>Rodents</topic><topic>Signaling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xia, Yunfeng</creatorcontrib><creatorcontrib>Entman, Mark L</creatorcontrib><creatorcontrib>Wang, Yanlin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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However, the molecular mechanisms underlying the recruitment of bone marrow-derived fibroblasts into the kidney are incompletely understood. Bone marrow-derived fibroblasts express the chemokine receptor--CCR2. In this study, we tested the hypothesis that CCR2 participates in the recruitment of fibroblasts into the kidney during the development of renal fibrosis. Bone marrow-derived collagen-expressing GFP⁺ fibroblasts were detected in the obstructed kidneys of chimeric mice transplanted with donor bone marrow from collagen α1(I)-GFP reporter mice. These bone marrow-derived fibroblasts expressed PDGFR-β and CCR2. CCR2 knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors expressing the hematopoietic marker-CD45 and the mesenchymal markers-PDGFR-β or procollagen I in the obstructed kidneys compared with wild-type mice. Furthermore, CCR2 knockout mice displayed fewer bone marrow-derived myofibroblasts and expressed less α-SMA or FSP-1 in the obstructed kidneys compared with wild-type mice. Consistent with these findings, genetic deletion of CCR2 inhibited total collagen deposition and suppressed expression of collagen I and fibronectin. Moreover, genetic deletion of CCR2 inhibits MCP-1 and CXCL16 gene expression associated with a reduction of inflammatory cytokine expression and macrophage infiltration, suggesting a linear interaction between two chemokines/ligand receptors in tubular epithelial cells. Taken together, our results demonstrate that CCR2 signaling plays an important role in the pathogenesis of renal fibrosis through regulation of bone marrow-derived fibroblasts. These data suggest that inhibition of CCR2 signaling could constitute a novel therapeutic approach for fibrotic kidney disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24130892</pmid><doi>10.1371/journal.pone.0077493</doi><tpages>e77493</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens Bone marrow Bone Marrow - pathology Bone marrow transplantation CC chemokine receptors CCR2 protein CD45 antigen Cell Line Chemokine CCL2 - genetics Chemokine CXCL16 Chemokine CXCL6 - genetics Chemokines Clonal deletion Collagen Collagen (type I) Collagen Type I - analysis CXCL16 protein Digital cameras Epithelial cells Fibroblasts Fibroblasts - metabolism Fibroblasts - pathology Fibronectin Fibronectins Fibrosis Gene Deletion Gene expression Gene Expression Regulation Genes Hemopoiesis Immunoglobulins Infiltration Inflammation Kidney - metabolism Kidney - pathology Kidney diseases Kidney Diseases - genetics Kidney Diseases - pathology Kidney transplantation Kidneys Laboratory animals Macrophages Medicine Mesenchyme Mice Mice, Inbred C57BL Mice, Knockout Molecular chains Molecular modelling Monocyte chemoattractant protein 1 Morphology Myofibroblasts - metabolism Myofibroblasts - pathology Nephrology Osteoprogenitor cells Pathogenesis Platelet-derived growth factor Procollagen Proteins Quantitative analysis Receptors Receptors, CCR2 - genetics Rodents Signaling |
| title | CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T21%3A41%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CCR2%20regulates%20the%20uptake%20of%20bone%20marrow-derived%20fibroblasts%20in%20renal%20fibrosis&rft.jtitle=PloS%20one&rft.au=Xia,%20Yunfeng&rft.date=2013-10-10&rft.volume=8&rft.issue=10&rft.spage=e77493&rft.pages=e77493-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0077493&rft_dat=%3Cgale_plos_%3EA478335445%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1441280902&rft_id=info:pmid/24130892&rft_galeid=A478335445&rft_doaj_id=oai_doaj_org_article_ab9e20931caa4e55818168aeec2e89f1&rfr_iscdi=true |