Complement Factor C5a Mediates Renal Ischemia-Reperfusion Injury Independent from Neutrophils

Vries, Bart de; Köhl, Jörg; Leclercq, Wouter K G; Wolfs, Tim G. A. M.; Bijnen, Annemarie A. J. H. M. van; Heeringa, Peter; Buurman, Wim A.

doi:10.4049/jimmunol.170.7.3883

Cited by 217 publications

(178 citation statements)

References 41 publications

(48 reference statements)

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“…In a previous study, de Vries et al (6) showed that C5a-mediated renal IRI in the mouse was independent of neutrophils. In this regard, it is of interest to note a dissociation between renal IRI and neutrophil infiltration in CVFtreated CD55 Ϫ/Ϫ CD59 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…Both anaphylatoxin-and MAC-mediated tubular injuries have been proposed as potential mechanisms for complement-dependent pathogenesis of renal IRI (6,8,9). Although we demonstrated that exacerbated renal IRI in CD55 Ϫ/Ϫ CD59 Ϫ/Ϫ mice was complement dependent, the mediator(s) responsible for the increased renal injury remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Zhou et al (8) demonstrated that the primary effect of complement in a murine model of renal IRI was on the tubular epithelial cells rather than on the vascular endothelium and that this effect was mainly attributed to the formation of MAC on the tubules. Other studies have shown that C5a is critically involved in the pathogenesis of renal IRI in the mouse through its modulation of both neutrophil-dependent and independent pathways (6,9).…”

mentioning

confidence: 99%

“…There is no clinically accepted therapeutic regimen that will ameliorate or prevent cellular injury after ischemia to the kidneys (2)(3)(4). Although the pathogenesis of human ATN is not fully understood, a number of studies in animals have shown that the complement system is one of the important mediators of renal ischemia reperfusion injury (IRI) (5)(6)(7)(8). Both anaphylatoxin (C3a, C5a)-dependent and membrane attack complex (MAC)-dependent mechanisms have been proposed for the complement role in animal models of renal IRI.…”

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confidence: 99%

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Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Yamada

Miwa

Liu

et al. 2004

The Journal of Immunology

153

135

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Renal ischemia-reperfusion injury (IRI) is a feature of ischemic acute renal failure and it impacts both short- and long-term graft survival after kidney transplantation. Complement activation has been implicated in renal IRI, but its mechanism of action is uncertain and the determinants of complement activation during IRI remain poorly understood. We engineered mice deficient in two membrane complement regulatory proteins, CD55 and CD59, and used them to investigate the role of these endogenous complement inhibitors in renal IRI. CD55-deficient (CD55−/−), but not CD59-deficient (CD59−/−), mice exhibited increased renal IRI as indicated by significantly elevated blood urea nitrogen levels, histological scores, and neutrophil infiltration. Remarkably, although CD59 deficiency alone was inconsequential, CD55/CD59 double deficiency greatly exacerbated IRI. Severe IRI in CD55−/−CD59−/− mice was accompanied by endothelial deposition of C3 and the membrane attack complex (MAC) and medullary capillary thrombosis. Complement depletion in CD55−/−CD59−/− mice with cobra venom factor prevented these effects. Thus, CD55 and CD59 act synergistically to inhibit complement-mediated renal IRI, and abrogation of their function leads to MAC-induced microvascular injury and dysfunction that may exacerbate the initial ischemic assault. Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55−/−CD59−/− mouse provides a useful animal model in this regard.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Yamada

Miwa

Liu

et al. 2004

The Journal of Immunology

153

135

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“…All of these compounds are potent CD88 antagonists in vitro; however, only the C5a mutants C5aRAM (24) and jun/fos-A8 (25), the cyclic peptide AcPhe[L-ornithinePro-D-cyclohexylalanine-Trp-Arg] (AcF-(OpdChaWR)) (29), and a nonpeptidic antagonist (23) have been proven useful in vivo. Administration of these inhibitors protects animals from in-flammatory responses in immune complex disease (25,29,30), ischemia/reperfusion injury (25,31,32), and C5a-induced neutropenia (23,24). The molecular mechanisms underlying the C5aR antagonism are largely unknown.…”

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confidence: 99%

C5a Mutants Are Potent Antagonists of the C5a Receptor (CD88) and of C5L2

Otto

Hawlisch

Monk

et al. 2004

Journal of Biological Chemistry

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The anaphylatoxin C5a exerts a plethora of biologic activities critical in the pathogenesis of systemic inflammatory diseases. Recently, we reported on a C5a mutant, jun/fos-A8, as a potent antagonist for the human and mouse C5a receptor (CD88). Addressing the molecular mechanism accounting for CD88 receptor antagonism by site-directed mutagenesis, we found that a positively charged amino acid at position 69 is crucial. Replacements by either hydrophobic or negatively charged amino acids switched the CD88 antagonist jun/fos-A8 to a CD88 agonist. In addition to CD88, the seven-transmembrane receptor C5L2 has recently been found to provide high affinity binding sites for C5a and its desarginated form, C5adesArg 74 . A jun/fos-A8 mutant in which the jun/ fos moieties and amino acids at positions 71-73 were deleted, A8 ⌬71-73 , blocked C5a and C5adesArg 74 binding to CD88 and C5L2. In contrast, the cyclic C5a C-terminal analog peptide AcF-[OP-D-ChaWR] inhibited binding of the two anaphylatoxins to CD88 but not to C5L2, suggesting that the C5a core segment is important for high affinity binding to C5L2. Both receptors are coexpressed on human monocytes and the human mast cell line HMC-1; however, C5L2 expression on monocytes is weaker as compared with HMC-1 cells and highly variable. In contrast, no C5L2 expression was found on human neutrophils. A8 ⌬71-73 is the first antagonist that blocks C5a and C5adesArg 74 binding to both C5a receptors, CD88 and C5L2, making it a valuable tool for studying C5L2 functions and for blocking the biological activities of C5a and C5adesArg 74 in mice and humans.

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