title: Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations.
abstract: Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemia-reperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b(+) cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis. The CD11b(+)/Ly6C(high) population associated with the onset of renal injury and increase in proinflammatory cytokines, whereas the CD11b(+)/Ly6C(intermediate) population peaked during kidney repair. The CD11b(+)/Ly6C(low) population emerged with developing renal fibrosis. Principal component and hierarchical cluster analyses identified gene signatures unique to each population. The CD11b(+)/Ly6C(intermediate) population had a distinct phenotype of wound healing, confirmed by results of studies inhibiting the macrophage colony-stimulating factor 1 receptor,whereas the CD11b(+)/Ly6C(low) population had a profibrotic phenotype. All populations, including the CD11b(+)/Ly6C(high) population, carried differential inflammatory signatures. The expression of M2-specific markers was detected in both the CD11b(+)/Ly6C(intermediate) and CD11b(+)/Ly6C(low) populations, suggesting these in vivo populations do not fit into the traditional classifications defined by in vitro systems. Results of this study in a renal ischemia-reperfusion injury model allow phenotype and function to be assigned to CD11b(+)/Ly6C(+) monocyte/macrophage populations in the pathophysiology of disease after AKI.
authors.affiliation: Tissue Protection and Repair Unit, Renal Science.
authors.forename: Meghan
authors.initials: M
authors.lastname: Clements
authors.affiliation: Tissue Protection and Repair Unit, Renal Science.
authors.forename: Michael
authors.initials: M
authors.lastname: Gershenovich
authors.affiliation: Tissue Protection and Repair Unit, Renal Science.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chaber
authors.affiliation: Flow Cytometry Core Facility, and.
authors.forename: Juanita
authors.initials: J
authors.lastname: Campos-Rivera
authors.affiliation: Functional Genomics, Genzyme R&D Center, Genzyme, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.affiliation: Functional Genomics, Genzyme R&D Center, Genzyme, a Sanofi Company, Framingham, Massachusetts.
authors.forename: Mindy
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Tissue Protection and Repair Unit, Renal Science.
authors.forename: Steve
authors.initials: S
authors.lastname: Ledbetter
authors.affiliation: Tissue Protection and Repair Unit, Renal Science, drazukphd@yahoo.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Zuk
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis*; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000145:classification*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse
keywords: fibrosis; gene expression; ischemia-reperfusion; macrophages; pathophysiology of renal disease and progression; transcriptional profiling