NDT Advance Access originally published online on September 5, 2007
Nephrology Dialysis Transplantation 2008 23(1):110-119; doi:10.1093/ndt/gfm563
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Intrarenal administration of recombinant human soluble thrombomodulin ameliorates ischaemic acute renal failure
1Department of Nephrology and 2Department of Urology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showaku, Nagoya, Japan 466-8550, Japan
Correspondence to: Dr Shoichi Maruyama, MD, Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showaku, Nagoya, Japan 466-8550, Japan. Email: marus{at}med.nagoya-u.ac.jp
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Abstract |
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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.
Keywords: apoptosis; blood flow; endothelium; ischaemia; thrombomodulin
Received for publication: 22. 8.06
Accepted in revised form: 24. 7.07
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