Effects of human soluble thrombomodulin on experimental glomerulonephritis.
BACKGROUND
Coagulation and inflammation are both important processes that contribute to glomerular injury. The present study was performed to evaluate the effects of recombinant human soluble thrombomodulin (RHS-TM) in a lethal model of thrombotic glomerulonephritis and to investigate the possible mechanisms.


METHODS
Thrombotic glomerulonephritis was induced in rats by administration of lipopolysaccharide and rabbit anti-rat glomerular basement membrane antibody. One hour later, RHS-TM or heparin was administered, and the histological findings, renal functions, and coagulation parameters were evaluated. To evaluate the contribution of carboxypeptidase R (CPR) to the results obtained in rats treated with RHS-TM, plasma CPR levels were measured. Then, carboxypeptidase inhibitor (CPI), which prevents the function of CPR, was administered.


RESULTS
Massive glomerular thrombosis and lung hemorrhage developed within five hours of disease induction, and all rats died within 24 hours. RHS-TM (3 mg/kg) prevented the progression of the disease and all rats survived. Heparin (250 U/kg/h) showed similar anti-thrombotic effect, but induced massive hemorrhage in the lungs or stomach. RHS-TM attenuated leukocyte/neutrophil infiltration in the glomerulus but heparin did not, suggesting that RHS-TM has anti-inflammatory properties. CPR levels in plasma were about threefold higher in rats treated with RHS-TM compared to those in rats treated with heparin. Furthermore, the inhibitory effect of RHS-TM on leukocyte/neutrophil infiltration was significantly diminished by injection of CPI.


CONCLUSIONS
RHS-TM effectively attenuates the injuries of thrombotic glomerulonephritis in rats. The results indicate that RHS-TM, in addition to its anti-thrombotic action, may exert its anti-inflammatory properties by converting proCPR to CPR, which then inactivates anaphylatoxins. RHS-TM is a potential novel therapeutic tool for thrombotic glomerular injury and related disorders.
Ikeguchi
Hiroshi
H
Internal Medicine III, Nagoya University School of Medicine, Nagoya, Japan.
Maruyama
Shoichi
S
Morita
Yoshiki
Y
Fujita
Yutaka
Y
Kato
Tomomi
T
Natori
Yasuhiro
Y
Akatsu
Hiroyasu
H
Campbell
William
W
Okada
Noriko
N
Okada
Hidechika
H
Yuzawa
Yukio
Y
Matsuo
Seiichi
S
D000706:Anaphylatoxins / Q000378:metabolism; D000818:Animals; D001777:Blood Coagulation; D001806:Blood Urea Nitrogen; D025901:Carboxypeptidase B2 / Q000097:blood; D015936:Complement C5a / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007958:Leukocyte Count; D001121:Lysine Carboxypeptidase / Q000097:blood; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000008:administration & dosage*; D013927:Thrombosis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology
D000706:Anaphylatoxins; D018180:Thrombomodulin; D015936:Complement C5a; D005337:Fibrin; D003404:Creatinine; D025901:Carboxypeptidase B2; D001121:Lysine Carboxypeptidase; D013917:Thrombin