Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis.

Autor:	Boudhabhay I; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France., Poillerat V; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France., Grunenwald A; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France., Torset C; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France., Leon J; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France., Daugan MV; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France., Lucibello F; Institut National de la Santé et de la Recherche Médicale U932, Paris Sciences et Lettres University, Institut Curie, Paris, France., El Karoui K; Service de Néphrologie et Transplantation Rénale, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, Paris, France., Ydee A; Pathology Department, Lille University Hospital (Centre Hospitalier Universitaire), Pathology Institute, Institut National de la Santé et de la Recherche Médicale UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team 'Mucins, Epithelial Differentiation and Carcinogenesis,' Lille University, Centre Hospitalier Universitaire Lille, Lille, France., Chauvet S; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France; Department of Nephrology, Georges Pompidou European Hospital, Paris, France., Girardie P; Intensive Care Department, Université de Lille, Centre Hospitalier Universitaire Lille, Lille, France., Sacks S; Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK., Farrar CA; Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK., Garred P; Laboratory of Molecular Medicine, Department of Clinical Immunology, University of Copenhagen, Copenhagen, Denmark., Berthaud R; Department of Pediatric Nephrology, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France., Le Quintrec M; Department of Nephrology and Kidney Transplantation, Centre Hospitalier Universitaire de Montpellier, Montpellier, France., Rabant M; Department of Pathology, Necker Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France., de Lonlay P; Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, Assistance Publique - Hôpitaux de Paris, Paris, France., Rambaud C; Service Médecine Légale, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris, Garches, France., Gnemmi V; Pathology Department, Lille University Hospital (Centre Hospitalier Universitaire), Pathology Institute, Institut National de la Santé et de la Recherche Médicale UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team 'Mucins, Epithelial Differentiation and Carcinogenesis,' Lille University, Centre Hospitalier Universitaire Lille, Lille, France., Fremeaux-Bacchi V; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France; Laboratory of Immunology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France., Frimat M; University of Lille, U995-LIRIC-Lille Inflammation Research International Center, Lille, France; Department of Nephrology, Lille University Hospital, Centre Hospitalier Universitaire, Lille, France., Roumenina LT; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France. Electronic address: lubka.roumenina@sorbonne-universite.fr.
Jazyk:	angličtina
Zdroj:	Kidney international [Kidney Int] 2021 Mar; Vol. 99 (3), pp. 581-597. Date of Electronic Publication: 2020 Nov 01.
DOI:	10.1016/j.kint.2020.09.033
Abstrakt:	Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney, likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies. (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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