[Renal protective effects of specific cyclooxygenase-2 inhibitor in rats with subtotal renal ablation].
OBJECTIVE
To investigate the renoprotective effect of specific cyclooxygenase-2 (COX-2) inhibitor rofecoxib and its possible mechanism of retarding progressive renal injury in rats with subtotal renal ablation.


METHODS
Rats were randomly divided into six groups: sham, subtotal renal ablation (SNX). SNX treated with rofecoxib (10 mg.kg(-1).d(-1)). SNX treated with indomethacin (2 mg.kg(-1).d(-1)). SNX treated with losartan (100 mg.kg(-1).d(-1)). SNX treated with rofecoxib and losartan. Blood pressure, urinary protein and thromboxane B(2) (TXB(2)) were measured at the 6th week after operation and morphological changes were examined with light microscopy. The mRNA expression of transforming growth factor-beta type I and type II receptors (TbetaRI, TbetaRII) was detected by way of reverse transcription polymerase chain reaction. The expression of plasminogen activator inhibitor type1 (PAI-1), fibronectin (FN) and angiotensin II type 1 receptor was examined utilizing Western blotting or immunohistochemistry.


RESULTS
The levels of urinary protein and TXB(2) as well as cortical COX-2 expression in SNX group were significantly increased while COX-1 expression remained undisturbed in comparison with those in sham group. The levels of systolic blood pressure and angiotensin II in renal cortex significantly increased. The expression of TbetaRI and TbetaRII mRNA, PAI-1 and AT1 protein was up-regulated. The glomerulosclerosis index (GSI) and tubular injury index were increased in SNX group. Rofecoxib significantly inhibited the increase in proteinuria and reduced GSI and tubular injury index. The expression of TbetaRI, TbetaRII and PAI-1 was down-regulated by 36.44%, 45.02% and 31.16% respectively, similar to the effect of losartan treatment. Indomethacin significantly decreased proteinuria and slightly reduced GSI. However the tubular injury index was exacerbated. Systolic blood pressure was not significantly blunted in the groups of rofecoxib and indomethacin. There was no significant additive effect of combined therapy with losartan and rofecoxib, though proteinuria was reduced to a lower level.


CONCLUSIONS
Rofecoxib attenuates proteinuria and retards the progressive renal injury in rats with subtotal renal ablation partly by inhibition of COX-2 activity and modulation of activation of renal renin-angiotensin system as well as the down-regulation of transforming growth factor-beta type I and type II receptors and PAI-1.
Kong
Wei-xin
WX
Department of Nephrology, Huashan Hospital of Fudan University, Shanghai 200040, China. weixinkong@hotmail.com
Ma
Ji
J
Gu
Yong
Y
Yang
Hai-chun
HC
Zuo
Yi-qin
YQ
Lin
Shan-yan
SY
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D009392:Nephrectomy; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones; D016212:Transforming Growth Factor beta / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D017395:Plasminogen Activator Inhibitor 1; D013450:Sulfones; D016212:Transforming Growth Factor beta; C116926:rofecoxib; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases