Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Kidney International |
| Vol/bind | 99 |
| Udgave nummer | 3 |
| Sider (fra-til) | 581-597 |
| Antal sider | 17 |
| ISSN | 0085-2538 |
| DOI | |
| Status | Udgivet - mar. 2021 |
Bibliografisk note
Funding Information:
LTR reports grants from CSL Behring, outside the submitted work. All the other authors declared no competing interests.
Funding Information:
The cytometric and microscopy analyses were performed at the Centre d'Histologie, d'Imagerie et de Cytom?trie (CHIC) and the Centre de Recherche des Cordeliers UMRS1138 (Paris, France). We are grateful to the CHIC team for the excellent technical assistance. CHIC is a member of the Universit? Pierre et Marie Curie Flow Cytometry Network. We are grateful for excellent technical assistance from the Centre d'Exp?rimentations Fonctionnelles team of the Centre de Recherche des Cordeliers and for their support with animal experimentation. We are grateful for the team of the Genom'IC platform, Institut Cochin, Institut National de la Sant? et de la Recherche M?dicale (INSERM) U1016, headed by Dr. F. Letourner for the next-generation sequencing analyses and the Biochemistry platform in Hospital Bichat Centre Recherche sur l'Inflammation?Paris for the evaluation of the renal function parameters in the blood and urine of the mice. This work was supported by the INSERM. IB received a fellowship from the Soci?t? Francophone de N?phrologie Dialyse et Transplantation. This work was presented in the form of abstract at the 17th European Meeting on Complement in Human Disease (EMCHD 2019), Madrid, Spain, 2019. LTR, IB, and MF designed the research. IB, VP, AG, CT, JL, MVD, and FL performed the research. KEK, AY, SC, PG, RB, MlQ, MR, PdL, CR, and VG provided patient samples and take care for the patients. LTR, IB, VP, AG, MVD, SS, CF, VF-B, and MF analyzed the data. PG provided vital reagents. IB, VP, AG, MF, and LTR wrote the manuscript.
Publisher Copyright:
© 2020 International Society of Nephrology
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