Effects of human soluble thrombomodulin on experimental glomerulonephritis

Hiroshi Ikeguchi, Shoichi Maruyama, Yoshiki Morita, Yutaka Fujita, Tomomi Kato, Yasuhiro Natori, Hiroyasu Akatsu, William Campbell, Noriko Okada, Hidechika Okada, Yukio Yuzawa, Seiichi Matsuo

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)490-501
Number of pages12
JournalKidney International
Volume61
Issue number2
DOIs
Publication statusPublished - 01-01-2002

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Glomerulonephritis
Carboxypeptidase B2
Heparin
Carboxypeptidases
Neutrophil Infiltration
Wounds and Injuries
Leukocytes
human THBD protein
Anti-Inflammatory Agents
Anaphylatoxins
Hemorrhage
Lung
Glomerular Basement Membrane
Lipopolysaccharides
Disease Progression
Stomach
Thrombosis
Rabbits
Inflammation
Kidney

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Ikeguchi, H., Maruyama, S., Morita, Y., Fujita, Y., Kato, T., Natori, Y., ... Matsuo, S. (2002). Effects of human soluble thrombomodulin on experimental glomerulonephritis. Kidney International, 61(2), 490-501. https://doi.org/10.1046/j.1523-1755.2002.00160.x
Ikeguchi, Hiroshi ; Maruyama, Shoichi ; Morita, Yoshiki ; Fujita, Yutaka ; Kato, Tomomi ; Natori, Yasuhiro ; Akatsu, Hiroyasu ; Campbell, William ; Okada, Noriko ; Okada, Hidechika ; Yuzawa, Yukio ; Matsuo, Seiichi. / Effects of human soluble thrombomodulin on experimental glomerulonephritis. In: Kidney International. 2002 ; Vol. 61, No. 2. pp. 490-501.
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Ikeguchi, H, Maruyama, S, Morita, Y, Fujita, Y, Kato, T, Natori, Y, Akatsu, H, Campbell, W, Okada, N, Okada, H, Yuzawa, Y & Matsuo, S 2002, 'Effects of human soluble thrombomodulin on experimental glomerulonephritis', Kidney International, vol. 61, no. 2, pp. 490-501. https://doi.org/10.1046/j.1523-1755.2002.00160.x

Effects of human soluble thrombomodulin on experimental glomerulonephritis. / Ikeguchi, Hiroshi; Maruyama, Shoichi; Morita, Yoshiki; Fujita, Yutaka; Kato, Tomomi; Natori, Yasuhiro; Akatsu, Hiroyasu; Campbell, William; Okada, Noriko; Okada, Hidechika; Yuzawa, Yukio; Matsuo, Seiichi.

In: Kidney International, Vol. 61, No. 2, 01.01.2002, p. 490-501.

Research output: Contribution to journalArticle

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T1 - Effects of human soluble thrombomodulin on experimental glomerulonephritis

AU - Ikeguchi, Hiroshi

AU - Maruyama, Shoichi

AU - Morita, Yoshiki

AU - Fujita, Yutaka

AU - Kato, Tomomi

AU - Natori, Yasuhiro

AU - Akatsu, Hiroyasu

AU - Campbell, William

AU - Okada, Noriko

AU - Okada, Hidechika

AU - Yuzawa, Yukio

AU - Matsuo, Seiichi

PY - 2002/1/1

Y1 - 2002/1/1

N2 - 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.

AB - 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.

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Ikeguchi H, Maruyama S, Morita Y, Fujita Y, Kato T, Natori Y et al. Effects of human soluble thrombomodulin on experimental glomerulonephritis. Kidney International. 2002 Jan 1;61(2):490-501. https://doi.org/10.1046/j.1523-1755.2002.00160.x