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, an 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 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.-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.

The Controversial C5a Receptor C5aR2: Its Role in Health and Disease

“…Proinflammatory properties of C5aR2 have been shown in experimental allergic asthma [65, 68], dextran sulfate sodium- (DSS-) induced acute colitis [67], thioglycollate-induced peritonitis and air-pouch inflammation [68], acute lung injury (AKI) [71], acute pyelonephritis [72], renal I/R injury [73], and sepsis [7]. In the mouse models of these diseases, depletion of C5aR2 alleviates the pathological symptoms, ameliorates acute inflammatory responses, and protects mice from severe tissue damage.…”

“…In models of AKI induced by LPS, immune complexes, or C5a, the detrimental effects of C5aRs were through extracellular histones release in the lung [71]. In the mouse model of bilateral renal I/R, C5aR2 deficiency provided both functional and structural protection against renal I/R injury, better than C5aR1 deficiency [73]. Both renal- and leukocyte-expressing C5aR2 contributed to the detrimental effects on the kidney.…”

The complex functioning of the complement system in xenotransplantation

“…C5a was shown to have a more significant impact on IRI than C3a, through regulation of pro‐inflammatory cytokines (IL‐1β, IL‐6, and IL‐8) . Both C5aR1 and C5aR2 contribute to IRI and neutrophil activation …”

“…91 Both C5aR1 and C5aR2 contribute to IRI and neutrophil activation. 92 Upregulation of complement activation during mouse kidney IRI is associated with impaired kidney function even one year later. 93…”

Xenotransplantation literature update, July/August 2019

“…1 Zhou et al 1 describe IRI, as "inevitable" throughout the entire process of transplant including donor organ procurement, organ transport, and transplantation into the patient. IRI involves multiple complement system factors including C3a, 17 C5a, 18 C5aR1, 19 and C5aR2, 19 responses. The MHC system is known to be highly polymorphic, and while the high level of homology between HLA and SLA allows human T-cell receptor (TcR) to bind to SLA molecules and trigger T-cell activation, [20][21][22][23] SLA can also trigger anti-HLA antibodies.…”