Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice.
Ischemia/reperfusion (I/R) injury of the kidney is a common cause of acute renal failure (ARF) and is associated with high morbidity and mortality in the intensive care unit. The mechanisms underlying I/R injury are complex. Studies have shown that complement activation contributes to the pathogenesis of I/R injury in the kidney, but the exact mechanisms of complement activation have not been defined. We hypothesized that complement activation in this setting occurs via the alternative pathway and that mice deficient in complement factor B, an essential component of the alternative pathway, would be protected from ischemic ARF. Wild-type mice suffered from a decline in renal function and had significant tubular injury, particularly in the outer medulla, after I/R. We found that factor B-deficient mice (fB(-/-)) developed substantially less functional and morphologic renal injury after I/R. Furthermore, control wild-type mice had an increase in tubulointerstitial complement C3 deposition and neutrophil infiltration in the outer medulla after I/R, whereas fB(-/-) mice demonstrated virtually no C3 deposition or neutrophil infiltration. Our results demonstrate that complement activation in the kidney after I/R occurs exclusively via the alternative pathway, and that selective inhibition of this pathway provides protection to the kidneys from ischemic ARF.
Thurman
Joshua M
JM
Division of Nephrology University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Ljubanovic
Danica
D
Edelstein
Charles L
CL
Gilkeson
Gary S
GS
Holers
V Michael
VM
D058186:Acute Kidney Injury / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001806:Blood Urea Nitrogen; D003176:Complement C3 / Q000378:metabolism; D003186:Complement C9 / Q000378:metabolism; D011415:Complement Factor B / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D003170:Complement Pathway, Alternative / Q000235:genetics*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology*
D003176:Complement C3; D003186:Complement C9; D011415:Complement Factor B