P140Ischemia reperfusion injury and resulting progressive kidney fibrosis are attenuated by complement deficiency

Background: Ischemia reperfusion injury (IRI) causes acute kidney injury (AKI) and is a relevant complication in major cardiac surgery. In addition AKI is frequent in solid organ transplantation (tx): after lung tx the incidence is 50% and after heart tx with 75% even higher. AKI increases morbidity and mortality and contributes to the progression to chronic kidney disease (CKD). During AKI the complement cascade is activated rapidly and subsequent myeloid cells infiltrate the kidney. The infiltrating cells as well as resident kidney cells express complement receptors activated by C3a and C5a. In this study, we present the distinct role of complement factors and their receptors in an IRI mouse model. Methods: Renal IRI was induced in mice deficient for C5aR, C3 and C5L2 and in wild type (WT; C57Bl/6) control mice by transient unilateral clipping of the right renal pedicle for 45 min. The renal morphology, the glomerular filtration rate (GFR), renal blood flow (RBF), expression of pro-fibrotic and pro-inflammatory markers and infiltrating leukocytes, as well as pro-inflammatory cytokines were analyzed four weeks after injury induction. Results: Renal IRI caused severe inflammation and fibrosis in addition to loss of peritubular capillaries with severley impaired renal microcirculation in WT mice. Complement deficiency reduced the tubulointerstitial fibrosis markedly. Especially, C5L2 deficient mice had less fibrosis and collagen deposition compared to WT mice. C3 deficient mice showed less tubular atrophy and fibrosis as well. Moreover, inflammatory cell infiltration was significantly decreased in all types of complement deficient mice compared to WT controls. Conclusion: C3 and also C5L2 deficiency attenuated IRI and chronic kidney disease and complement inhibition might be a promising therapeutic target to prevent early inflammation as well as later fibrosis.