Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Abstract

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.

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

“…Reperfusion injury of ischemic skeletal muscle and intestinal epithelia has been found to invoke the classical pathway of complement in a natural Ab-dependent manner (10 -12). In contrast, renal IRI has been shown to depend on the alternative pathway of complement, as factor B-deficient, but not C4-deficicent mice, were protected from renal IRI (7,8). Though the evidence of complement participation in IRI is compelling, the role of membrane complement regulatory proteins in this process remains to be characterized.…”

“…Currently, evidence is accumulating for a pathological role of the complement system in renal and other types of IRI (5,(7)(8)(9). Why the complement system tends to be activated under the setting of IR and what are the factors that influence complement activation during this process are interesting questions that remain to be fully addressed.…”

“…A recent study showed that mice deficient in the complement protein factor B were protected from renal IRI, suggesting that complement activation via the alternative pathway played an important role in this process (7). However, in other models of IRI, both classical pathway-and lectin pathway-dependent mechanisms have been implicated (10 -13).…”

“…There is no clinically accepted therapeutic regimen that will ameliorate or prevent cellular injury after ischemia to the kidneys (2)(3)(4). Although the pathogenesis of human ATN is not fully understood, a number of studies in animals have shown that the complement system is one of the important mediators of renal ischemia reperfusion injury (IRI) (5)(6)(7)(8). Both anaphylatoxin (C3a, C5a)-dependent and membrane attack complex (MAC)-dependent mechanisms have been proposed for the complement role in animal models of renal IRI.…”

Absence of functional alternative complement pathway alleviates lupus cerebritis

“…In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined.…”