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


CONCLUSIONS
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.
Ozaki
Takenori
T
Department of Nephrology, Nagoya University Graduate School of Medicine, Showaku, Nagoya, Japan 466-8550, Japan.
Anas
Chabouk
C
Maruyama
Shoichi
S
Yamamoto
Tokunori
T
Yasuda
Kaoru
K
Morita
Yoshiki
Y
Ito
Yasuhiko
Y
Gotoh
Momokazu
M
Yuzawa
Yukio
Y
Matsuo
Seiichi
S
D058186:Acute Kidney Injury / Q000150:complications / Q000188:drug therapy*; D000818:Animals; D007511:Ischemia / Q000150:complications / Q000188:drug therapy*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D018180:Thrombomodulin / Q000627:therapeutic use*