Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury

Felix Poppelaars, Maaike B van Werkhoven, Juha Kotimaa, Zwanida J Veldhuis, Albertina Ausema, Stefan G M Broeren, Jeffrey Damman, Julia C. Hempel, Henri G D Leuvenink, Mohamed R Daha, Willem J van Son, Cees van Kooten, Ronald P van Os, Jan-Luuk Hillebrands, Marc A Seelen

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26 Citations (Scopus)

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, an in vivo migration 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 C5aR2 vs. leukocyte-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.

Original languageEnglish
Pages (from-to)3193-3204
Number of pages12
JournalThe FASEB Journal
Volume31
Issue number7
Early online date10-Apr-2017
DOIs
Publication statusPublished - Jul-2017

Keywords

  • innate immunity
  • PMNs
  • kidney
  • ACUTE KIDNEY INJURY
  • DONOR BRAIN-DEATH
  • ISCHEMIA/REPERFUSION INJURY
  • CHEMOATTRACTANT RECEPTOR
  • 2 PARTS
  • C5L2
  • ACTIVATION
  • CELLS
  • ANAPHYLATOXIN
  • PATHWAY

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