A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats.
BACKGROUND
C5a has been implicated in numerous pathophysiological conditions, including ischemia/reperfusion (I/R) injury of the kidney. We examined whether a novel and specific C5a receptor antagonist, the cyclic compound AcF-[OPdChaWR] could moderate I/R-induced renal injury in rats.


METHODS
Female Wistar rats were subjected to renal ischemia (60 min) and reperfusion (5 h). Rats were treated with either 1 mg/kg IV in 5% ethanol/saline or 10 mg/kg PO in 25% ethanol/saline prior to ischemia. I/R injury was characterized by significant tissue hemorrhage with increased microvascular permeability, elevated renal tissue levels of tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO), increased serum levels of creatinine and aspartate aminotransferase (AST) and hematuria.


RESULTS
Pre-ischemic treatment with the C5a receptor (C5aR) antagonist (1 mg/kg IV or 10 mg/kg PO) substantially inhibited or prevented I/R-induced hematuria, vascular leakage, tissue levels of TNF-alpha and MPO, and serum levels of AST and creatinine. Histological examination of kidneys from antagonist pretreated I/R animals showed a marked reduction in tissue damage compared to drug-free I/R rats. This antagonist, however, did not inhibit complement-mediated lysis of red blood cells, suggesting unimpaired formation of the membrane attack complex (MAC).


CONCLUSIONS
The results demonstrate for the first time that a selective antagonist of both human and rat C5a receptors, given either intravenously or orally, significantly protects the kidney from I/R injury in the rat. We conclude that C5a is an important pathogenic agent in renal I/R injury, and that C5a receptor antagonists may be useful therapeutic agents for the pretreatment of anticipated renal reperfusion injury in humans.
Arumugam
Thiruma V
TV
Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
Shiels
Ian A
IA
Strachan
Anna J
AJ
Abbenante
Giovani
G
Fairlie
David P
DP
Taylor
Stephen M
SM
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers; D015938:Complement Membrane Attack Complex; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology; D008833:Microcirculation; D010456:Peptides, Cyclic / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014556:Urine / Q000166:cytology
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D015415:Biomarkers; D015938:Complement Membrane Attack Complex; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine; D009195:Peroxidase; D001219:Aspartate Aminotransferases