C5aR2 Deficiency Improves Renal Regeneration after Renal Ischemia Reperfusion Injury and in Kidney Transplantation in Mice

Abstract

ObjectiveThe complement receptors C5aR1 and C5aR2 serve distinct roles in immune regulation. In kidney transplantation ischemia reperfusion injury (IRI) results in rapid complement activation. In this study C5aR1 and C5aR2 deficient mice were tested in a model of renal ischemia reperfusion injury (IRI) and in an isogenic cross over kidney transplantation (ktx) model.MethodsIRI was induced by unilateral clipping of renal pedicle for 45 min in C5aR1, C5aR2 −/− and wild type mice (WT). Renal morphology, inflammation, peritubular capillary density and renal fibrosis were investigated by immunohistochemistry. FACS analysis was done at d7 after IRI to analyze infiltrating subsets of myeloid and lymphocytes. To study renal perfusion impairment due to IRI arterial spin labelling was done. In a second model isogenic ktx with prolonged cold ischemia time of 90 min was performed and C5aR1−/−, C5aR2−/− or WT mice served as donors or recipients.ResultsWT mice showed dramatic decrease of renal perfusion and severe inflammation resulting in interstitial fibrosis at three weeks after IRI with substantial loss of kidney volume. C5aR2 −/− mice had less inflammation and started to regenerate at 7 days after IRI. Renal fibrosis was attenuated in C5aR2−/− mice which had less rarefication of peritubular capillaries compared to WT IRI kidneys. In the ktx model C5aR2 −/− of the recipient showed the best renal morphology with attenuated renal ischemia reperfusion injury of the graft. By FACS analysis differential activation in γδ‐Tcells in C5aR2 deficient mice was observed and may have contributed to enhanced regeneration.ConclusionC5aR2 deficiency attenuates renal damage and fibrosis in renal IRI and ktx by better regeneration and protection of capillary integrity of the renal tissue.