环氧合酶-2抑制剂对梗阻性肾病大鼠肾组织结缔组织生长因子表达的影响

Celecoxib inhibitor suppresses the expression of connective tissue growth factor in rats with unilateral ureteral obstruction(UUO) model by up-regulation cAMP

目的:探讨环氧合酶-2(COX-2)抑制剂塞来昔布(celecoxib)对梗阻性肾病大鼠模型肾组织结缔组织生长因子(CTGF)和转化生长因子β1(TGF-β1)表达的影响及机制。方法:采用单侧输尿管结扎(UUO)建立梗阻性肾病模型,并随机分为模型组和治疗组,另设假手术组作对照。治疗组每日给予塞来昔布100mg/kg,模型组、假手术组每日给予等体积的生理盐水于造模前1d至造模后14d灌胃,分别于UUO后3d、7d、14d分批处死,逆转录聚合酶链式反应(RT-PCR)检测TGF-β1、CTGF的基因表达,免疫组化技术检测TGF-β1、CTGF、α-SMA、FN的蛋白表达,放免法检测组织内cAMP的水平。结果:与假手术组相比,模型组TGF-β1、CTGF的基因表达显著上调,cAMP的水平下降(P<0.001)。塞来昔布对梗阻肾TGF-β1的表达无显著改变,但能升高组织内cAMP水平,抑制CTGF的表达,纤维化程度减轻。结论:在梗阻性肾病大鼠中TGF-β1、CTGF的表达均显著升高,选择性COX-2抑制剂通过升高组织内clip的水平来抑制TGF-B的下游因子———TGF的表达延缓肾间质纤维化。

objective To investigate the expression of connective tissue growth factor(CTGF) in rats with unilateral ureteral obstruction(UUO) model and mechanism of selective cyclooxygenase-2 inhibitor celecoxib suppresses tubulointerstitial fibrosis. Methods The UUO models were induced by ligating the left ureter. Forty-five wister rats were randomly divided into celecoxib (celecoxib 100mg/(kg·d) by gastric gavage from 24 h before the obstrction to day 14 after the induction), model and sham operation group. All rats were sacrificed at 3 d ,7 d ,14 d after UUO was initiated respectivety. The expression of transforming growth factor -beta 1 (TGF-β1) ,connective tissue growth factor (CTGF), α-SMA, FN and content of cAMP were examined reverse transcription ploymerase chain reaction (RT-PCR), immunohistochemical stainning and RIA(radioimmuno-assay) respectively. Similar studies were performed in another group of TGF-β1,CTGF were marleedly increased in model group of rats with sham operation. Results The mRNA expression of TGF-β1 and CTGF were markedly increased in another group(UUO 3 d, P< 0.05, UUO 6d and UUO 14d, P< 0.001). With a higher centent of cAMP, the expression of CTGF, α-SMA and FN were inhibited in group celecoxib compared model group, but the expression of TGF-β1 was not different(P >0 05). Conclusions Selective cyclooxygenase-2 inhibitor celecoxib has a salutary effection on tubular and interstitial response to UUO through domn-regulation of CTGF by increasing levels of cAMP.