Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

1. J Am Soc Nephrol. 2015 Jun;26(6):1363-77. doi: 10.1681/ASN.2014040320. Epub
2014 Sep 30.

Specific macrophage subtypes influence the progression of rhabdomyolysis-induced
kidney injury.

Belliere J(1), Casemayou A(2), Ducasse L(2), Zakaroff-Girard A(3), Martins F(4),
Iacovoni JS(5), Guilbeau-Frugier C(6), Buffin-Meyer B(2), Pipy B(7), Chauveau
D(1), Schanstra JP(8), Bascands JL(8).

Author information:
(1)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;
(2)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;
(3)Cytometry and Cell-sorting Platform, INSERM/Unité Mixte de Recherche U1048,
Toulouse, France;
(4)Genome and Transcriptome Platform, Toulouse Genopole INSERM/Unité Mixte de
Recherche U1048, University Paul Sabatier, Toulouse, France;
(5)Bioinformatic Platform, INSERM/Unité Mixte de Recherche U1048, University
Paul Sabatier, Toulouse, France;
(6)Université de Toulouse III Paul Sabatier, Toulouse, France; Department of
Pathology, Toulouse University Hospital, Rangueil, Toulouse, France; and.
(7)Unité Mixte de Recherche 152, Macrophages Polarization and Nuclear Receptors,
Toulouse, France.
(8)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;
.

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.

Copyright © 2015 by the American Society of Nephrology.

DOI: 10.1681/ASN.2014040320
PMCID: PMC4446873
PMID: 25270069 [Indexed for MEDLINE]

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