特异性环氧合酶-2抑制剂对肾大部切除鼠进行性肾损害的保护作用

Renal protective effects of specific cyclooxygenase-2 inhibitor in rats with subtotal renal ablation

目的 探讨特异性环氧合酶 2 (COX 2 )抑制剂罗非昔布 (rofecoxib)延缓肾大部切除大鼠进行性肾损害的机制。方法 将大鼠随机分为假手术组、肾大部切除组 (SNX)、罗非昔布组、吲哚美辛组、氯沙坦组、罗非昔布与氯沙坦合用组 ,每组 6只。 6周后检测大鼠血压、尿蛋白及尿血栓素B2(TXB2 )的排泄量 ,观察肾组织病理改变 ,检测肾皮质血管紧张素Ⅱ (AngⅡ )浓度 ,应用免疫组化的方法检测纤维连接蛋白 (FN)的表达 ,逆转录 聚合酶链反应 (RT PCR)法检测转化生长因子 βⅠ型受体(TβRⅠ )及Ⅱ型受体 (TβRⅡ )的mRNA表达 ,免疫印迹法检测肾皮质COX 2、COX 1、纤溶酶原激活物抑制剂 1 (PAI 1 )及血管紧张素 1型受体 (AT1 )的表达。结果 与假手术组相比 ,SNX组大鼠尿蛋白及肾皮质COX 2的表达与尿TXB2 排泄明显增多 ,COX 1表达无明显变化 ;系统血压及AngⅡ浓度明显增高 ,肾皮质TβRⅠ及TβRⅡ的mRNA及PAI 1和AT1的表达显著上调 ,肾小球硬化指数及小管间质损伤指数增高。罗非昔布能明显减轻蛋白尿 (P <0 0 5)、减轻肾小球硬化指数及肾小管间质损伤指数(P <0 0 5) ,肾皮质TβRⅠ、TβRⅡ和PAI 1的表达较SNX组分别下调 36 44%、45 0 2 %和 31 1 6 % ,与氯沙坦作用相当。

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 β typeⅠand typeⅡ receptors (TβRI, TβRⅡ) was detected by way of reverse transcription polymerase chain reaction The expression of plasminogen activator inhibitor type1 (PAI 1)?fibronectin (FN) and angiotensinⅡ 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 angiotensinⅡin renal cortex significantly increased The expression of TβRⅠand TβRⅡmRNA, 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 TβRⅠ, TβRⅡ 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 Conclusion 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 β typeⅠand typeⅡ receptors and PAI 1