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

Boudhabhay, Idris; Poillerat, Victoria; Grünenwald, Anne; Torset, Carine; Léon, Juliette; Daugan, Marie V.; Lucibello, Francesca; Karoui, Khalil El; Ydée, Amandine; Chauvet, Sophie; Girardie, Patrick; Sacks, Steven; Farrar, Conrad A.; Garred, Peter; Berthaud, Romain; Quintrec, Moglie Le; Rabant, Marion; Lonlay, Pascale de; Rambaud, Caroline; Gnemmi, Viviane; Frémeaux‐Bacchi, Véronique; Frimat, Marie; Roumenina, Lubka T.

doi:10.1016/j.kint.2020.09.033

Cited by 62 publications

(56 citation statements)

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“…Myoglobin and CK are the main products of the breakdown of skeletal muscle bres in a glycerol-induced RM model [30]. Myoglobin-induced renal toxicity plays a key role in RM-induced AKI by activating the complement system and increasing oxidative stress, in ammation, endothelial dysfunction, vasoconstriction, and apoptosis [10][11][12]. The clinical symptoms of RM are characterised by elevated serum CK and myoglobin [1].…”

Section: Discussionmentioning

confidence: 99%

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Exogenous biological renal support improves kidney function in rhabdomyolysis-induced acute kidney injury in mice

Liu

Chi

Geng

et al. 2021

Preprint

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BackgroundRhabdomyolysis (RM) is a clinical syndrome characterised by the breakdown of skeletal muscle fibres and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous study, exogenous biological renal support alleviates renal ischaemia-reperfusion injury (IRI) in elderly mice. This study aimed to determine whether exogenous biological renal support promoted renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved.MethodsA parabiosis animal model was established to investigate effects of exogenous biological renal support on RM-induced AKI. Male wild-type C57BL/6 mice and C57BL/6-TgN (ACTb-EGFP) transgenic mice were used to determine whether shared circulation was established among parabiotic pairs 3 weeks after parabiosis surgery. Mice were divided into three groups: the control group (sterile saline injected); RM group (glycerol (8 mL/kg) injected); and parabiosis + RM group (three weeks after the parabiosis model was established, the recipient mouse was injected with glycerol). Blood samples and kidney tissue were collected for further processing 48 hours after RM induction. Bioinformatics analysis was conducted with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, functional enrichment analysis and clustering analysis.ResultsAt 48 hours after the procedure, all mice survived. Exogenous biological renal support attenuated the histological and functional deterioration in RM-induced AKI in mice. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated kidney injury through multiple pathways, including suppressing the complement system; attenuating oxidative stress, inflammation, and apoptosis; and increasing proliferation.ConclusionsExogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and apoptosis; and promoting tubular cell proliferation. Our study provides new ideas for effectively preventing and treating RM-induced AKI and provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.

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Section: Discussionmentioning

confidence: 99%

“…Myoglobin and its oxygen-carrying moiety haem play a key role in the development of AKI. AKI can cause renal tubular obstruction, renal vasoconstriction, and the direct activation of oxidative stress, lipid peroxidation and macrophages, which injure proximal tubular cells [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Exogenous biological renal support improves kidney function in rhabdomyolysis-induced acute kidney injury in mice

Liu

Chi

Geng

et al. 2021

Preprint

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“…Similar to endothelial cells, such adverse effects are reported with other cell types when massively exposed to heme. This is the case for human skeletal muscle fibers, in which exposure to heme induces contractile dysfunction [ 29 ], and renal tubular cells [ 30 ]. In addition, iron is notably toxic even at low concentrations.…”

Section: About Heme Oxygenase-1 In Kidneymentioning

confidence: 99%

“…The mechanism for kidney injuries is classically described as an association of renal vasoconstriction [ 157 ], proximal tubular aggression (by oxidative stress, lipid peroxidation [ 158 , 159 ] and macrophage activation [ 160 , 161 ]) and intra-tubular precipitation of myoglobin. Recently, complement has also been reported to play a contributory role—in a partly heme-dependent manner—in RIAKI [ 30 , 162 ].…”

Section: Ho-1 In Kidney Diseasesmentioning

confidence: 99%

“…Receptor for advanced glycation end-products (RAGE) has also been confirmed as a receptor for heme [175] and is expressed in tubular cells [176]-it will be interesting to explore its role in RIAKI. Expression of HO-1 was reported to be independent of complement system activation in RIAKI, since HO-1 was upregulated equally in both wild type and C3 −/− mice injected with glycerol, despite reduced kidney lesions in C3 −/− mice [30].…”

Section: Rhabdomyolysismentioning

confidence: 99%

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Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

Grünenwald

Roumenina

Frimat

2021

IJMS

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The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney’s filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1’s functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1’s role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.

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The complement system in pediatric acute kidney injury

et al. 2022

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The complement cascade is an important part of the innate immune system. In addition to helping the body to eliminate pathogens, however, complement activation also contributes to the pathogenesis of a wide range of kidney diseases. Recent work has revealed that uncontrolled complement activation is the key driver of several rare kidney diseases in children, including atypical hemolytic uremic syndrome and C3 glomerulopathy. In addition, a growing body of literature has implicated complement in the pathogenesis of more common kidney diseases, including acute kidney injury (AKI). Complement-targeted therapeutics are in use for a variety of diseases, and an increasing number of therapeutic agents are under development. With the implication of complement in the pathogenesis of AKI, complement-targeted therapeutics could be trialed to prevent or treat this condition. In this review, we discuss the evidence that the complement system is activated in pediatric patients with AKI, and we review the role of complement proteins as biomarkers and therapeutic targets in patients with AKI.

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

Cited by 62 publications

References 50 publications

Exogenous biological renal support improves kidney function in rhabdomyolysis-induced acute kidney injury in mice

Exogenous biological renal support improves kidney function in rhabdomyolysis-induced acute kidney injury in mice

Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

The complement system in pediatric acute kidney injury

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