Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis
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Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. / Boudhabhay, Idris; Poillerat, Victoria; Grunenwald, Anne; Torset, Carine; Leon, Juliette; Daugan, Marie V.; Lucibello, Francesca; El Karoui, Khalil; Ydee, Amandine; Chauvet, Sophie; Girardie, Patrick; Sacks, Steven; Farrar, Conrad A.; Garred, Peter; Berthaud, Romain; Le Quintrec, Moglie; Rabant, Marion; de Lonlay, Pascale; Rambaud, Caroline; Gnemmi, Viviane; Fremeaux-Bacchi, Veronique; Frimat, Marie; Roumenina, Lubka T.
In: Kidney International, Vol. 99, No. 3, 03.2021, p. 581-597.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis
AU - Boudhabhay, Idris
AU - Poillerat, Victoria
AU - Grunenwald, Anne
AU - Torset, Carine
AU - Leon, Juliette
AU - Daugan, Marie V.
AU - Lucibello, Francesca
AU - El Karoui, Khalil
AU - Ydee, Amandine
AU - Chauvet, Sophie
AU - Girardie, Patrick
AU - Sacks, Steven
AU - Farrar, Conrad A.
AU - Garred, Peter
AU - Berthaud, Romain
AU - Le Quintrec, Moglie
AU - Rabant, Marion
AU - de Lonlay, Pascale
AU - Rambaud, Caroline
AU - Gnemmi, Viviane
AU - Fremeaux-Bacchi, Veronique
AU - Frimat, Marie
AU - Roumenina, Lubka T.
N1 - Publisher Copyright: © 2020 International Society of Nephrology
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - C3 deposition
KW - complement
KW - heme
KW - hemopexin
KW - lectin pathway
KW - rhabdomyolysis-induced acute kidney injury
U2 - 10.1016/j.kint.2020.09.033
DO - 10.1016/j.kint.2020.09.033
M3 - Journal article
C2 - 33137339
AN - SCOPUS:85096740846
VL - 99
SP - 581
EP - 597
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 3
ER -
ID: 285877872