Complement Receptor C5L2 Improves Renal Perfusion Impairment after Ischemia Reperfusion Injury

Abstract

Objective Ischemia reperfusion injury (IRI) causes acute kidney injury (AKI) which is a relevant complication in major cardiac surgery. IRI causes rapid complement activation and C5a activation which signals via the C5aR and the C5a like 2 (C5L2) receptor. Currently, little is known about the differences between these two receptors. Methods IRI was induced in C5L2 and C5aR deficient and wild type mice (WT) by unilateral clipping of the right renal pedicle for 45 min. Renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by inulin and PAH clearance. Renal morphology, inflammation and renal fibrosis were investigated by immunohistochemistry. In addition FACS analysis was done to quantify leukocyte subsets at day 7. Functional MRI studies to analyze RBF were performed at different time points (d1, d7, week3). Results Complement receptor deficiency attenuated inflammation and macrophage infiltration after IRI. In addition, collagen deposition was sig reduced in C5L2-/- mice compared to WT and C5aR-/- mice. Functional MRI revealed similar impairment of RBF at d1 but much better recovery at d7 and week 3 in C5L2-/- mice compared to WT. Decreased renal perfusion correlated with severe kidney volume loss. This was line with PAH clearance measurements. Inflammatory cell infiltration analysed by FACS showed similar activation of myeloid cells but revealed differences in activation of gd T-cells in C5L2-/- mice. Conclusion The complement receptor C5L2 is an important mediator for the recovery of renal microcirculation after IRI and affects renal fibrosis. Complement targeted therapies might be promising in prevention of AKI.