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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3781-3787
Activated protein C reduces ischemia/reperfusion-induced renal
injury in rats by inhibiting leukocyte activation
Akio Mizutani,
Kenji Okajima,
Mitsuhiro Uchiba, and
Takayuki Noguchi
From the Department of Anesthesiology, Oita Medical University, and
the Department of Laboratory Medicine, Kumamoto University School of
Medicine, Kumamoto, Japan.
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- (TNF-), 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-.
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