Effects of human soluble thrombomodulin on experimental glomerulonephritis.

Abstract

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.

CONCLUSION:

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.

• Authors: Hiroshi Ikeguchi, Shoichi Maruyama, Yoshiki Morita, Yutaka Fujita, Tomomi Kato, Yasuhiro Natori, Hiroyasu Akatsu, William Campbell, Noriko Okada, Hidechika Okada, Yukio Yuzawa, Seiichi Matsuo
• Journal: Kidney international (Kidney Int) Vol. 61 Issue 2 Pg. 490-501 (Feb 2002) ISSN: 0085-2538 [Print] United States
• PMID: 11849389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anaphylatoxins
• Thrombomodulin
• Complement C5a
• Fibrin
• Creatinine
• Carboxypeptidase B2
• Lysine Carboxypeptidase
• Thrombin

Topics

• Anaphylatoxins (metabolism)
• Animals
• Blood Coagulation
• Blood Urea Nitrogen
• Carboxypeptidase B2 (blood)
• Complement C5a (metabolism)
• Creatinine (blood)
• Disease Models, Animal
• Female
• Fibrin (metabolism)
• Glomerulonephritis (drug therapy, etiology, pathology)
• Humans
• Kidney Glomerulus (metabolism, pathology)
• Leukocyte Count
• Lysine Carboxypeptidase (blood)
• Partial Thromboplastin Time
• Platelet Count
• Prothrombin Time
• Rabbits
• Rats
• Rats, Wistar
• Solubility
• Thrombin (metabolism)
• Thrombomodulin (administration & dosage)
• Thrombosis (chemically induced, complications, pathology)