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Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation by Akio Mizutani, Kenji Okajima, Mitsuhiro.

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Presentation on theme: "Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation by Akio Mizutani, Kenji Okajima, Mitsuhiro."— Presentation transcript:

1 Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation by Akio Mizutani, Kenji Okajima, Mitsuhiro Uchiba, and Takayuki Noguchi Blood Volume 95(12): June 15, 2000 ©2000 by American Society of Hematology

2 Changes in serum levels of blood urea nitrogen (BUN) and creatinine in rats after renal ischemia and reperfusion (I/R).Rats were subjected to uninephrectomy and 60 minutes of renal ischemia followed by reperfusion. Changes in serum levels of blood urea nitrogen (BUN) and creatinine in rats after renal ischemia and reperfusion (I/R).Rats were subjected to uninephrectomy and 60 minutes of renal ischemia followed by reperfusion. Serum levels of BUN (A) and creatinine (B) were measured before ischemia (Pre), and 3, 6, 12, and 24 hours after reperfusion. Rats in the sham-operation group had uninephrectomy but not I/R. Data are expressed as mean ± SD values. Open circles indicate rats in the sham-operation group (n = 5); and closed circles, rats that had I/R (n = 5). *P < .01 compared with the sham-operation group. Akio Mizutani et al. Blood 2000;95: ©2000 by American Society of Hematology

3 Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on I/R-induced increases in BUN and creatinine.Serum levels of BUN (A) and creatinine (B) were measured 24 hours after reperfusion in rats subjected to 60 minutes of renal ischemia followed by r... Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on I/R-induced increases in BUN and creatinine.Serum levels of BUN (A) and creatinine (B) were measured 24 hours after reperfusion in rats subjected to 60 minutes of renal ischemia followed by reperfusion. Animals were intravenously administered saline, APC (100 μg/kg of body weight), DEGR-FXa (1 mg/kg), heparin (300 U/kg), or DIP-APC (100 μg/kg) 30 minutes before reperfusion. Leukocytopenia was induced by administration of nitrogen mustard. Data are expressed as mean ± SD values. Values in parentheses indicate the number of animals in each experiment. *P < .01 compared with the sham-operation group; †P < .01 compared with the I/R plus saline group. Akio Mizutani et al. Blood 2000;95: ©2000 by American Society of Hematology

4 Akio Mizutani et al. Blood 2000;95:3781-3787
©2000 by American Society of Hematology

5 Akio Mizutani et al. Blood 2000;95:3781-3787
©2000 by American Society of Hematology

6 Changes in serum levels of FDP(E) in rats that had renal I/R, and effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on I/R-induced increases in serum levels of FDP(E) 24 hours after reperfusion.(A) Rats were subjected to uninephrectomy and 60 m... Changes in serum levels of FDP(E) in rats that had renal I/R, and effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on I/R-induced increases in serum levels of FDP(E) 24 hours after reperfusion.(A) Rats were subjected to uninephrectomy and 60 minutes of renal ischemia followed by reperfusion. Serum levels of FDP(E) were measured before ischemia (Pre), and 3, 6, 12, 24, and 48 hours after reperfusion. Rats in the sham-operation group had uninephrectomy only. Data are expressed as mean ± SD values. Open circles indicate rats in the sham-operation group (n = 5); and closed circles, rats that had I/R (n = 5). *P < .01 compared with the sham-operation group. (B) Rats were given intravenously administered saline, APC (100 μg/kg), DEGR-FXa (1 mg/kg), heparin (300 U/kg), or DIP-APC (100 μg/kg) 30 minutes before reperfusion. Leukocytopenia was induced by administration of nitrogen mustard. Data are expressed as mean ± SD values. Values in parentheses indicate the number of animals in each experiment. *P < .01 compared with the sham-operation group; †P < .01 compared with the I/R plus saline group. Akio Mizutani et al. Blood 2000;95: ©2000 by American Society of Hematology

7 Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the renal I/R-induced decrease in renal tissue blood flow in rats.Rats were subjected to 60 minutes of renal ischemia followed by reperfusion. Effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the renal I/R-induced decrease in renal tissue blood flow in rats.Rats were subjected to 60 minutes of renal ischemia followed by reperfusion. Renal tissue blood flow was measured from 30 minutes before ischemia until 3 hours after reperfusion. Data are expressed as mean ± SD values from 5 experiments. Closed circles indicate saline-treated rats; open circles, APC-treated rats; closed squares, DEGR-FXa–treated rats; open squares, heparin-treated rats; closed triangles, DIP-APC–treated rats; and open triangles, leukocytopenic rats. *P < .01 compared with saline-treated rats that had I/R. Akio Mizutani et al. Blood 2000;95: ©2000 by American Society of Hematology

8 Changes in renal vascular permeability in rats after renal I/R, and effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the I/R-induced increase in vascular permeability observed 6 hours after reperfusion.(A) Rats were subjected to uninephrect... Changes in renal vascular permeability in rats after renal I/R, and effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the I/R-induced increase in vascular permeability observed 6 hours after reperfusion.(A) Rats were subjected to uninephrectomy and 60 minutes of renal ischemia followed by reperfusion. Renal vascular permeability was evaluated by assessing leakage of Evans blue dye administered intravenously 10 minutes before the rats were killed. Vascular permeability was measured before ischemia (Pre) and 3, 6, 12, and 24 hours after reperfusion. Data are expressed as mean ± SD values. Open circles indicate rats in the sham-operation group (n = 5), and closed circles, rats that had I/R (n = 5). *P < .01 compared with the sham-operation group. (B) Rats were given intravenously administered saline, APC (100 μg/kg), DEGR-FXa (1 mg/kg), heparin (300 U/kg), or DIP-APC (100 μg/kg) 30 minutes before reperfusion. Leukocytopenia was induced by administration of nitrogen mustard. Data are expressed as mean ± SD values. Values in parentheses indicate the number of animals in each experiment. *P < .01 compared with the sham-operation group; †P < .01 compared with the I/R plus saline group. Akio Mizutani et al. Blood 2000;95: ©2000 by American Society of Hematology

9 Changes in renal tissue levels of cytokines and MPO after renal I/R in rats and effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia.Shown are the renal tissue levels of tumor necrosis factor-α (TNF-α) (A), rat interleukin 8 (IL-8) (B), and MPO (C... Changes in renal tissue levels of cytokines and MPO after renal I/R in rats and effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia.Shown are the renal tissue levels of tumor necrosis factor-α (TNF-α) (A), rat interleukin 8 (IL-8) (B), and MPO (C) after renal I/R and the effects of APC, DEGR-FXa, heparin, DIP-APC, and leukocytopenia on the I/R-induced increases in renal tissue levels of TNF-α (D), rat IL-8 (E), and MPO (F) after reperfusion. Renal tissue levels of TNF-α, rat IL-8, and MPO were measured before ischemia (Pre) and 3, 6, 12, and 24 hours after reperfusion or sham operation. Renal tissue levels of TNF-α and rat IL-8 were measured 3 hours after reperfusion; renal tissue levels of MPO were determined 6 hours after reperfusion. Data are expressed as mean ± SD values. Values in parentheses indicate the number of rats in each experiment. *P < .01 compared with the sham-operation group; †P < .01 compared with the I/R plus saline group. Akio Mizutani et al. Blood 2000;95: ©2000 by American Society of Hematology

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