title: CSF-1 signaling mediates recovery from acute kidney injury.
abstract: Renal tubule epithelia represent the primary site of damage in acute kidney injury (AKI), a process initiated and propagated by the infiltration of macrophages. Here we investigated the role of resident renal macrophages and dendritic cells in recovery from AKI after ischemia/reperfusion (I/R) injury or a novel diphtheria toxin-induced (DT-induced) model of selective proximal tubule injury in mice. DT-induced AKI was characterized by marked renal proximal tubular cell apoptosis. In both models, macrophage/dendritic cell depletion during the recovery phase increased functional and histologic injury and delayed regeneration. After I/R-induced AKI, there was an early increase in renal macrophages derived from circulating inflammatory (M1) monocytes, followed by accumulation of renal macrophages/dendritic cells with a wound-healing (M2) phenotype. In contrast, DT-induced AKI only generated an increase in M2 cells. In both models, increases in M2 cells resulted largely from in situ proliferation in the kidney. Genetic or pharmacologic inhibition of macrophage colony-stimulating factor (CSF-1) signaling blocked macrophage/dendritic cell proliferation, decreased M2 polarization, and inhibited recovery. These findings demonstrated that CSF-1-mediated expansion and polarization of resident renal macrophages/dendritic cells is an important mechanism mediating renal tubule epithelial regeneration after AKI.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ming-zhi.zhang@vanderbilt.edu
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Suwan
authors.initials: S
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Fan
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
authors.forename: Karlton
authors.initials: K
authors.lastname: Wong
authors.forename: Tomoki
authors.initials: T
authors.lastname: Miyazawa
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Chang
authors.forename: Amar
authors.initials: A
authors.lastname: Singh
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D000818:Animals; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology; D004167:Diphtheria Toxin; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D020127:Recovery of Function; D012038:Regeneration; D015398:Signal Transduction
chemical_list: D004167:Diphtheria Toxin; D011993:Recombinant Fusion Proteins; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor