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 lipopolysaccharide (LPS). We hypothesized that LPS could induce tubular synthesis and secretion of C3, leading to activation of the complement cascade and direct renal tubular injury.


METHODS
ARF was induced in mice by intravenous injection of LPS and was confirmed 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 recombinant protein containing the potent murine complement C3 activation inhibitor Crry was injected at the same time as LPS (N = 8). (2) LPS was injected 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 immunofluorescence (IF) microscopy in mice injected with LPS was greater in renal cortical tubular cells (IF score of 2. 1 +/- 0.1 vs. 1.4 +/- 0.2 in controls, P = 0.013), 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 experiment did BUN values correlate with the extent of C3 staining.


CONCLUSIONS
Although LPS up-regulates renal C3 synthesis, resulting in basolateral tubular C3 deposition, this is not responsible for LPS-induced ARF in mice.
Cunningham
P N
PN
Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637, USA.
Holers
V M
VM
Alexander
J J
JJ
Guthridge
J M
JM
Carroll
M C
MC
Quigg
R J
RJ
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000209:etiology / Q000276:immunology*; D000419:Albuminuria; D000818:Animals; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D003176:Complement C3 / Q000235:genetics / Q000652:urine*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000235:genetics; D017463:Receptors, Complement 3b; D011993:Recombinant Fusion Proteins / Q000235:genetics; D018805:Sepsis / Q000150:complications
D003176:Complement C3; C081470:Cr1l protein, mouse; D018950:Lipopolysaccharide Receptors; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011993:Recombinant Fusion Proteins