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Ischemia reperfusion injury (IRI) contributes to acute kidney injury (AKI) and to delayed graft function which can be up to 50% due to prolonged cold ischemia time kidney transplantation. A hallmark of IRI is activation of the comeplement system but so far, there is little known about the different roles of the two C5a receptors (C5aR1 versus C5aR2). In this study C5aR1 and C5aR2 deficient mice were investigated used in the renal IRI model and different pathological responses were by longitudinal monitoring.Unilateral IRI of 45 min was done in C5aR1, C5aR2 -/- and wild type mice (WT). Renal morphology, inflammation, regeneration and renal fibrosis were investigated by immunohistochemistry and qPCR. To measure renal perfusion functional magnetic resonance imaging (MRI) was done at day 1, 7 and 21. Renal tissue was processed for high content antibody microarrays and differential total protein and phospho protein expression was analyzed. Based on the proteomics results AKT and p-AKT protein expression in the tissue was investigated by Western blotting.Extensive renal fibrosis was detected in WT mice within 3 weeks after IRI whereas C5aR deficienct mice showed partial protection. Especially, C5aR2 deficient mice showed enhanced tubular proliferation measured by Ki-67 expression and improved renal perfusion over time.Macrophage infiltration was attenuated in C5aR2 -/- mice and the transcript of the anti-inflammatory cytokine IL-10 was significantly up-regulated. Moreover, proteomics revealed significantly enhanced phosphorylation of the pro-angiogenic FGF1 in C5aR2-/- IRI kidneys at d1. In addition, total AKT protein and consecutively also phospho-AKT was significantly higher in C5aR2-/- compared to the other mouse strains.C5aR2 deficient mice have enhanced p-FGF and p-AKT levels after IRI which might have contributed to improved regeneration of peritubular capillaries, tubular epithelial cells and better renal perfusion.