title: CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America ; Division of Nephrology, Department of Medicine, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Xia
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000235:genetics; D024042:Collagen Type I / Q000032:analysis; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics*
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D024042:Collagen Type I; C498926:Cxcl16 protein, mouse; D054390:Receptors, CCR2