title: Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors.
abstract: Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR)4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-α, transforming growth factor (TGF)-β1, and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-α and TGF-β1 levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4(+) immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO-induced fibrosis. There was also reduced total kidney TGF-β1, which correlated with reduced Smad activation and α-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-β1 and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis.
authors.affiliation: Department of Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Amy
authors.initials: A
authors.lastname: Yuan
authors.affiliation: Department of Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Yashang
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
authors.forename: Uimook
authors.initials: U
authors.lastname: Choi
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut; and.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.affiliation: Department of Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut anil.karihaloo@yale.edu anil.karihaloo@astrazeneca.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Karihaloo
mesh_terms: D000818:Animals; D001596:Benzylamines; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D000080027:Cyclams; D005355:Fibrosis; D006571:Heterocyclic Compounds; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation; D008297:Male; D008810:Mice, Inbred C57BL; D009400:Nephrosclerosis / Q000209:etiology* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D014517:Ureteral Obstruction
chemical_list: D001596:Benzylamines; D055419:Bone Morphogenetic Protein 7; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C525820:bmp7 protein, mouse; C088327:plerixafor
keywords: AMD-3100; bone morphogenetic protein 7; chemokine (C-X-C motif) receptor 4; fibrosis; kidney; macrophages