title: Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury.
abstract: Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France; Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, Toulouse, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Belliere
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Audrey
authors.initials: A
authors.lastname: Casemayou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Laure
authors.initials: L
authors.lastname: Ducasse
authors.affiliation: Cytometry and Cell-sorting Platform, INSERM/Unité Mixte de Recherche U1048, Toulouse, France;
authors.forename: Alexia
authors.initials: A
authors.lastname: Zakaroff-Girard
authors.affiliation: Genome and Transcriptome Platform, Toulouse Genopole INSERM/Unité Mixte de Recherche U1048, University Paul Sabatier, Toulouse, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Martins
authors.affiliation: Bioinformatic Platform, INSERM/Unité Mixte de Recherche U1048, University Paul Sabatier, Toulouse, France;
authors.forename: Jason S
authors.initials: JS
authors.lastname: Iacovoni
authors.affiliation: Université de Toulouse III Paul Sabatier, Toulouse, France; Department of Pathology, Toulouse University Hospital, Rangueil, Toulouse, France; and.
authors.forename: Céline
authors.initials: C
authors.lastname: Guilbeau-Frugier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Buffin-Meyer
authors.affiliation: Unité Mixte de Recherche 152, Macrophages Polarization and Nuclear Receptors, Toulouse, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France; Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, Toulouse, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France; jean-loup.bascands@inserm.fr joost-peter.schanstra@inserm.fr.
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France; Université de Toulouse III Paul Sabatier, Toulouse, France; jean-loup.bascands@inserm.fr joost-peter.schanstra@inserm.fr.
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009211:Myoglobin / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D012206:Rhabdomyolysis / Q000150:complications* / Q000503:physiopathology*; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D009211:Myoglobin; D004002:Clodronic Acid; D005990:Glycerol
keywords: Immunology and pathology; acute renal failure; chronic kidney disease; fibrosis; macrophages.; rhabdomyolysis