title: Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury.
abstract: The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR injury; however, the role of C5aR2 in IR injury is less clear as initial studies proposed the hypothesis that C5aR2 functions as a decoy receptor. By Using wild-type, C5aR1-/-, and C5aR2-/-mice in a model of renal IR injury, we found that a deficiency of either of these receptors protected mice from renal IR injury. Surprisingly, C5aR2-/-mice were most protected and had lower creatinine levels and reduced acute tubular necrosis. Next, anin vivomigration study demonstrated that leukocyte chemotaxis was unaffected in C5aR2-/-mice, whereas neutrophil activation was reduced by C5aR2 deficiency. To further investigate the contribution of renal cell-expressed C5aR2vsleukocyte-expressed C5aR2 to renal IR injury, bone marrow chimeras were created. Our data show that both renal cell-expressed C5aR2 and leukocyte-expressed C5aR2 mediate IR-induced renal dysfunction. These studies reveal the importance of C5aR2 in renal IR injury. They further show that C5aR2 is a functional receptor, rather than a decoy receptor, and may provide a new target for intervention.-Poppelaars, F., van Werkhoven, M. B., Kotimaa, J., Veldhuis, Z. J., Ausema, A., Broeren, S. G. M., Damman, J., Hempel, J. C., Leuvenink, H. G. D., Daha, M. R., van Son, W. J., van Kooten, C., van Os, R. P., Hillebrands, J.-L., Seelen, M. A. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Felix
authors.initials: F
authors.lastname: Poppelaars
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Maaike B
authors.initials: MB
authors.lastname: van Werkhoven
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Kotimaa
authors.affiliation: Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Zwanida J
authors.initials: ZJ
authors.lastname: Veldhuis
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Albertina
authors.initials: A
authors.lastname: Ausema
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Stefan G M
authors.initials: SGM
authors.lastname: Broeren
authors.affiliation: Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Damman
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Hempel
authors.affiliation: Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Henri G D
authors.initials: HGD
authors.lastname: Leuvenink
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.|Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van Son
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: van Os
authors.affiliation: Division of Pathology, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; m.seelen@umcg.nl.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Seelen
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000209:etiology*; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: C000591759:C5ar1 protein, mouse; C000594938:C5ar2 protein, mouse; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a
keywords: PMNs; innate immunity; kidney