Complement is activated in kidney by endotoxin but does not cause the ensuing acute renal failure

Background. Acute renal failure (ARF) in sepsis occurs when the release of multiple inflammatory mediators is induced by bacterial endotoxins. C3 mRNA is markedly up-regulated in mouse kidney after exposure to lipopolysacchar ide (LPS). We hypothesized that LPS could induce tubular synthesis and secr etion of C3, leading to activation of the complement cascade and direct ren al tubular injury. Methods. ARF was induced in mice by intravenous injection of LPS and was co nfirmed by an acute rise in blood urea nitrogen (BUN) and histologically by acute tubular necrosis. Three separate strategies were used to investigate the role of the complement system in this model of ARF: (1) Crry-Ig, a rec ombinant protein containing the potent murine complement C3 activation inhi bitor Crry was injected at the same time as LPS (N = 8). (2) LPS was inject ed into transgenic mice overexpressing Crry in glomeruli and tubules (N = 8 ), and (3) LPS was injected into C3-deficient mice (N = 5). Results. Compared with unmanipulated mice, C3 staining by immunofluorescenc e (IF) microscopy in mice injected with LPS was greater in renal cortical t ubular cells (IF score of 2.1 +/- 0.1 vs. 1.4 +/- 0.2 in controls, P = 0.01 3), most prominently at the basolateral surface. LPS injection led to a 16- to 42-fold increase in urinary C3 excretion. Despite reduction or complete elimination of renal C3 with maneuvers suppressing complement activation, BUN values were not statistically different across all groups. In no experi ment did BUN values correlate with the extent of C3 staining. Conclusion. Although LPS up-regulates renal C3 synthesis, resulting in baso lateral tubular C3 deposition, this is not responsible for LPS-induced ARF in mice.