Figure 3

Role of complement in renal ischemia-reperfusion injury, inflammation, and progression to kidney fibrosis. Ischemia-reperfusion injury activates the complement system by release of endogenous ligands (DAMPs) from acutely injured tissue. The formation of the membrane attack complex (MAC) results in direct injury to the kidney by inducing apoptosis in epithelial tubular cells. In addition, the cleavage of C3 and C5 and subsequent release of anaphylatoxins (C3a and C5a) promotes inflammatory cell recruitment and release of pro-inflammatory cytokines/chemokines and reactive oxygen species, intensifying the immune response and further amplifying the level of tubular necrosis and apoptosis. Activated endothelium, monocytes and injured tubular epithelium have all been shown to secrete pro-fibrogenic factors such as TGF-β and PDGF in response to C3aR and C5aR ligation by C3a and C5a, respectively, which in turn activates local fibroblasts inducing collagen deposition and tissue repair. Dysregulated activation of complement and the subsequent inflammatory response ultimately results in maladaptive tissue repair and fibrosis.