A functional role for complement receptor C5L2 in the pathogenesis of renal ischemia-reperfusion injury

Abstract

The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The two receptors for C5a, C5aR and C5L2, are expressed on leukocytes as well as in the kidney. Extensive evidence shows that C5aR inhibition protects kidneys from IR injury, but the role of C5L2 in IR injury has not been studied so far. Therefore, WT, C5aR−/− and C5L2−/− mice were subjected to 40 min of bilateral renal ischemia, followed by reperfusion for 1, 3 or 7 days. It was found that C5L2−/− mice were protected against IR injury, resulting in significant lower plasma creatinine and BUN levels, and reduced acute tubular necrosis. Next, an in vivo migration study, where WT, C5aR−/− and C5L2−/− mice were injected intraperitoneally with complement ligands, revealed that C5L2 is not involved in leukocyte migration. To investigate the contribution of renal-expressed C5L2 versus leukocyte-expressed C5L2 to renal IR injury, bone marrow chimeras were created. Our data show that renal-expressed C5L2 and leukocyte-expressed C5L2 mediate IR injury-induced renal dysfunction. Therefore, C5L2 is a functional receptor in renal IR injury rather than a simple decoy receptor. For that reason, next to C5aR, C5L2 is a potential target for intervention during renal IR injury.