Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation.
BACKGROUND
Complement has been implicated in the pathophysiology of renal ischemia-reperfusion (I/R) injury. However, the mechanism underlying complement-mediated renal I/R injury is thus far unknown. To investigate the involvement of complement in I/R injury, we studied the activation and deposition of complement in a murine model of renal I/R injury. Furthermore, we examined the effect of inhibition of complement-factor C5 on renal I/R injury.


METHODS
Mice were subjected to 45 min of unilateral ischemia and subsequent contralateral nephrectomy and reperfusion for 2, 12, or 24 hr. Mice were control treated or treated with BB5.1, a monoclonal antibody that prevents cleavage of complement factor C5, thereby preventing C5a generation and formation of the membrane attack complex (MAC).


RESULTS
Renal I/R induced extensive deposition of C3 early after reperfusion, whereas C6 and C9 deposition (MAC formation) occurred relatively late. I/R-induced complement deposition was mainly localized to tubular epithelium. Treatment with BB5.1 totally prevented MAC formation but also reduced C3 deposition. Inhibition of C5 strongly inhibited late inflammation, as measured by neutrophil influx and induction of the murine CXC chemokines macrophage inflammatory protein-2, KC, and lipopolysaccharide-induced CXC chemokine. Anti-C5 treatment furthermore abrogated late I/R-induced apoptosis, whereas early apoptosis was not affected. Moreover, BB5.1 treatment significantly protected against I/R-induced renal dysfunction.


CONCLUSIONS
Renal I/R is followed by activation of the complement system and intrarenal deposition of C3 and MAC. Complement activation plays a crucial role in the regulation of inflammation and late apoptosis. Complement inhibition, by preventing C5 activation, abrogates late apoptosis and inflammation, being strongly protective against renal function loss.
De Vries
Bart
B
Department of General Surgery, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands.
Matthijsen
Robert A
RA
Wolfs
Tim G A M
TG
Van Bijnen
Annemarie A J H M
AA
Heeringa
Peter
P
Buurman
Wim A
WA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001806:Blood Urea Nitrogen; D003167:Complement Activation; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000032:analysis; D003404:Creatinine / Q000097:blood; D007668:Kidney / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D009393:Nephritis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
D000911:Antibodies, Monoclonal; D003182:Complement C5; D015938:Complement Membrane Attack Complex; D003404:Creatinine