Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure

Takenori Ozaki, Chabouk Anas, Shoichi Maruyama, Tokunori Yamamoto, Kaoru Yasuda, Yoshiki Morita, Yasuhiko Ito, Momokazu Gotoh, Yukio Yuzawa, Seiichi Matsuo

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background. Thrombomodulin (TM) is an endothelial anti-coagulant cofactor which also has anti-inflammatory properties. The present study was performed to investigate the effects of recombinant human soluble TM (RHS-TM) on ischaemia/reperfusion (I/R) renal injury. Methods. A right nephrectomy was performed in rats, and the left kidney was filled with RHS-TM (0.25 mg/kg), argatroban (20 mg/kg) or a vehicle for 45 min. Before reperfusion, the fluid trapped in the kidney was completely removed. At 24 h after I/R, renal cortical blood flow was measured using a CCD video camera, and the kidneys were harvested for the study. Next, cultured human umbilical vein endothelial cells were treated with RHS-TM (2, 10 or 50 mg/ml) or a vehicle, and incubated for 5 h in culture medium containing 300 μM hydrogen peroxide. Apoptotic cell death was analysed by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Results. Immunohistochemistry revealed that the level of TM expression decreased in rat kidneys after I/R. RHS-TM significantly decreased blood urea nitrogen and serum creatinine levels. It also prevented a reduction in cortical blood flow, and attenuated tubular damage and macrophage/neutrophil infiltration. In addition, the number of TUNEL-positive cells decreased significantly in rats treated with RHS-TM. In contrast, argatroban, an inhibitor of thrombin did not show significant renoprotective actions. The results of in vitro study showed that RHS-TM significantly suppressed the number of apoptotic cells. Conclusion. The transient intrarenal administration of RHS-TM, but not argatroban, to the kidney attenuates I/R renal injury. The present study suggests that RHS-TM would be a useful tool in preventing transplanted kidney damage or treating acute renal failure in the clinical setting.

Original languageEnglish
Pages (from-to)110-119
Number of pages10
JournalNephrology Dialysis Transplantation
Volume23
Issue number1
DOIs
Publication statusPublished - 01-01-2008

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Acute Kidney Injury
Kidney
Thrombomodulin
Reperfusion Injury
Reperfusion
Coagulants
DNA Nucleotidylexotransferase
Neutrophil Infiltration
human THBD protein
Renal Circulation
Blood Urea Nitrogen
Human Umbilical Vein Endothelial Cells
Transferases
Nephrectomy
Thrombin
Hydrogen Peroxide
Culture Media
Creatinine
Cell Death
Anti-Inflammatory Agents

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Transplantation

Cite this

Ozaki, Takenori ; Anas, Chabouk ; Maruyama, Shoichi ; Yamamoto, Tokunori ; Yasuda, Kaoru ; Morita, Yoshiki ; Ito, Yasuhiko ; Gotoh, Momokazu ; Yuzawa, Yukio ; Matsuo, Seiichi. / Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure. In: Nephrology Dialysis Transplantation. 2008 ; Vol. 23, No. 1. pp. 110-119.
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abstract = "Background. Thrombomodulin (TM) is an endothelial anti-coagulant cofactor which also has anti-inflammatory properties. The present study was performed to investigate the effects of recombinant human soluble TM (RHS-TM) on ischaemia/reperfusion (I/R) renal injury. Methods. A right nephrectomy was performed in rats, and the left kidney was filled with RHS-TM (0.25 mg/kg), argatroban (20 mg/kg) or a vehicle for 45 min. Before reperfusion, the fluid trapped in the kidney was completely removed. At 24 h after I/R, renal cortical blood flow was measured using a CCD video camera, and the kidneys were harvested for the study. Next, cultured human umbilical vein endothelial cells were treated with RHS-TM (2, 10 or 50 mg/ml) or a vehicle, and incubated for 5 h in culture medium containing 300 μM hydrogen peroxide. Apoptotic cell death was analysed by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Results. Immunohistochemistry revealed that the level of TM expression decreased in rat kidneys after I/R. RHS-TM significantly decreased blood urea nitrogen and serum creatinine levels. It also prevented a reduction in cortical blood flow, and attenuated tubular damage and macrophage/neutrophil infiltration. In addition, the number of TUNEL-positive cells decreased significantly in rats treated with RHS-TM. In contrast, argatroban, an inhibitor of thrombin did not show significant renoprotective actions. The results of in vitro study showed that RHS-TM significantly suppressed the number of apoptotic cells. Conclusion. The transient intrarenal administration of RHS-TM, but not argatroban, to the kidney attenuates I/R renal injury. The present study suggests that RHS-TM would be a useful tool in preventing transplanted kidney damage or treating acute renal failure in the clinical setting.",
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Ozaki, T, Anas, C, Maruyama, S, Yamamoto, T, Yasuda, K, Morita, Y, Ito, Y, Gotoh, M, Yuzawa, Y & Matsuo, S 2008, 'Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure', Nephrology Dialysis Transplantation, vol. 23, no. 1, pp. 110-119. https://doi.org/10.1093/ndt/gfm563

Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure. / Ozaki, Takenori; Anas, Chabouk; Maruyama, Shoichi; Yamamoto, Tokunori; Yasuda, Kaoru; Morita, Yoshiki; Ito, Yasuhiko; Gotoh, Momokazu; Yuzawa, Yukio; Matsuo, Seiichi.

In: Nephrology Dialysis Transplantation, Vol. 23, No. 1, 01.01.2008, p. 110-119.

Research output: Contribution to journalArticle

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T1 - Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure

AU - Ozaki, Takenori

AU - Anas, Chabouk

AU - Maruyama, Shoichi

AU - Yamamoto, Tokunori

AU - Yasuda, Kaoru

AU - Morita, Yoshiki

AU - Ito, Yasuhiko

AU - Gotoh, Momokazu

AU - Yuzawa, Yukio

AU - Matsuo, Seiichi

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Background. Thrombomodulin (TM) is an endothelial anti-coagulant cofactor which also has anti-inflammatory properties. The present study was performed to investigate the effects of recombinant human soluble TM (RHS-TM) on ischaemia/reperfusion (I/R) renal injury. Methods. A right nephrectomy was performed in rats, and the left kidney was filled with RHS-TM (0.25 mg/kg), argatroban (20 mg/kg) or a vehicle for 45 min. Before reperfusion, the fluid trapped in the kidney was completely removed. At 24 h after I/R, renal cortical blood flow was measured using a CCD video camera, and the kidneys were harvested for the study. Next, cultured human umbilical vein endothelial cells were treated with RHS-TM (2, 10 or 50 mg/ml) or a vehicle, and incubated for 5 h in culture medium containing 300 μM hydrogen peroxide. Apoptotic cell death was analysed by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Results. Immunohistochemistry revealed that the level of TM expression decreased in rat kidneys after I/R. RHS-TM significantly decreased blood urea nitrogen and serum creatinine levels. It also prevented a reduction in cortical blood flow, and attenuated tubular damage and macrophage/neutrophil infiltration. In addition, the number of TUNEL-positive cells decreased significantly in rats treated with RHS-TM. In contrast, argatroban, an inhibitor of thrombin did not show significant renoprotective actions. The results of in vitro study showed that RHS-TM significantly suppressed the number of apoptotic cells. Conclusion. The transient intrarenal administration of RHS-TM, but not argatroban, to the kidney attenuates I/R renal injury. The present study suggests that RHS-TM would be a useful tool in preventing transplanted kidney damage or treating acute renal failure in the clinical setting.

AB - Background. Thrombomodulin (TM) is an endothelial anti-coagulant cofactor which also has anti-inflammatory properties. The present study was performed to investigate the effects of recombinant human soluble TM (RHS-TM) on ischaemia/reperfusion (I/R) renal injury. Methods. A right nephrectomy was performed in rats, and the left kidney was filled with RHS-TM (0.25 mg/kg), argatroban (20 mg/kg) or a vehicle for 45 min. Before reperfusion, the fluid trapped in the kidney was completely removed. At 24 h after I/R, renal cortical blood flow was measured using a CCD video camera, and the kidneys were harvested for the study. Next, cultured human umbilical vein endothelial cells were treated with RHS-TM (2, 10 or 50 mg/ml) or a vehicle, and incubated for 5 h in culture medium containing 300 μM hydrogen peroxide. Apoptotic cell death was analysed by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Results. Immunohistochemistry revealed that the level of TM expression decreased in rat kidneys after I/R. RHS-TM significantly decreased blood urea nitrogen and serum creatinine levels. It also prevented a reduction in cortical blood flow, and attenuated tubular damage and macrophage/neutrophil infiltration. In addition, the number of TUNEL-positive cells decreased significantly in rats treated with RHS-TM. In contrast, argatroban, an inhibitor of thrombin did not show significant renoprotective actions. The results of in vitro study showed that RHS-TM significantly suppressed the number of apoptotic cells. Conclusion. The transient intrarenal administration of RHS-TM, but not argatroban, to the kidney attenuates I/R renal injury. The present study suggests that RHS-TM would be a useful tool in preventing transplanted kidney damage or treating acute renal failure in the clinical setting.

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