Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation.
We examined whether activated protein C (APC) reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. In a rat model, intravenous administration of APC markedly reduced I/R-induced renal dysfunction and histological changes, whereas intravenous administration of dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-FXa; active-site-blocked factor Xa), heparin or diisopropyl fluorophosphate-treated APC (DIP-APC; inactive derivative of ARC) had no effect. Furthermore, APC significantly inhibited the I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability, whereas neither DEGR-FXa, heparin, nor DIP-APC produced such effects. Renal I/R-induced increases in plasma levels of fibrin degradation products were significantly inhibited by APC, DEGR-FXa, and heparin. These observations suggest that APC reduces I/R-induced renal injury independently of its anticoagulant effects but in a manner dependent on its serine protease activity. Renal levels of tumor necrosis factor-alpha (TNF-alpha), rat interleukin-8, and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by APC but not by DEGR-FXa, heparin, or DIP-APC. Leukocytopenia produced effects similar to those of APC. These findings strongly suggest that APC protects against I/R-induced renal injury not by inhibiting coagulation abnormalities but by inhibiting activation of leukocytes that play an important role in I/R-induced renal injury. Inhibition of leukocyte activation by APC could be explained by the inhibitory activity of TNF-alpha. (Blood. 2000;95:3781-3787)
Mizutani
A
A
Department of Anesthesiology, Oita Medical University, Japan.
Okajima
K
K
Uchiba
M
M
Noguchi
T
T
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015951:Factor Xa / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007531:Isoflurophate / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D016207:Cytokines; D016209:Interleukin-8; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; D007531:Isoflurophate; D006493:Heparin; D009195:Peroxidase; D015951:Factor Xa