Kong Wei-xin, Ma Ji, Gu Yong, Yang Hai-chun, Zuo Yi-qin, Lin Shan-yan
Department of Nephrology, Huashan Hospital of Fudan University, Shanghai 200040, China.
Zhonghua Nei Ke Za Zhi. 2003 Mar;42(3):186-90.
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.
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.
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.
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.
探讨特异性环氧化酶-2（COX-2）抑制剂罗非昔布对肾大部切除大鼠的肾脏保护作用及其延缓进行性肾损伤的可能机制。
将大鼠随机分为六组：假手术组、肾大部切除（SNX）组、罗非昔布（10 mg·kg⁻¹·d⁻¹）治疗的SNX组、吲哚美辛（2 mg·kg⁻¹·d⁻¹）治疗的SNX组、氯沙坦（100 mg·kg⁻¹·d⁻¹）治疗的SNX组、罗非昔布与氯沙坦联合治疗的SNX组。术后第6周测量血压、尿蛋白和血栓素B₂（TXB₂），并通过光学显微镜检查形态学变化。采用逆转录聚合酶链反应检测转化生长因子-βⅠ型和Ⅱ型受体（TβRI、TβRII）mRNA表达。利用蛋白质印迹法或免疫组织化学检测纤溶酶原激活物抑制剂1（PAI-1）、纤连蛋白（FN）和血管紧张素Ⅱ1型受体表达。
与假手术组相比，SNX组尿蛋白和TXB₂水平以及皮质COX-2表达显著升高，而COX-1表达未受影响。肾皮质收缩压和血管紧张素Ⅱ水平显著升高。TβRI和TβRII mRNA、PAI-1和AT1蛋白表达上调。SNX组肾小球硬化指数（GSI）和肾小管损伤指数升高。罗非昔布显著抑制蛋白尿增加，降低GSI和肾小管损伤指数。TβRI、TβRII和PAI-1表达分别下调36.44%、45.02%和31.16%，与氯沙坦治疗效果相似。吲哚美辛显著降低蛋白尿，轻微降低GSI。然而，肾小管损伤指数加重。罗非昔布和吲哚美辛组收缩压无显著降低。氯沙坦与罗非昔布联合治疗虽蛋白尿降至较低水平，但无显著相加作用。
罗非昔布部分通过抑制COX-2活性、调节肾素-血管紧张素系统激活以及下调转化生长因子-βⅠ型和Ⅱ型受体及PAI-1，减轻肾大部切除大鼠蛋白尿并延缓进行性肾损伤。
