不同剂量环氧合酶-2抑制剂对梗阻性肾病大鼠肾间质纤维化的影响

目的:观察环氧合酶-2(COX2)抑制剂塞来昔布对梗阻性肾病大鼠模型肾间质纤维化的影响及其机制。方法:大鼠采用单侧输尿管结扎(UUO)建立梗阻性肾病模型。给药组大鼠自造模前1 d至造模后7 d分别给予塞来昔布5 mg·kg-1·d-1、10 mg·kg-1·d-1、30 mg·kg-1·d-1灌胃,另设模型组和假手术组给予等体积的0.9%氯化钠溶液灌胃作为对照(n=10)。RT-PCR检测结缔组织生长因子(connective tissue growth factor,CTGF)的基因表达,免疫组化技术检测CTGF、平滑肌肌动蛋白(smooth-muscle actin,α-SMA)、纤维连接蛋白(fibronectin,FN)的蛋白表达,放免法检测血浆内血管紧张素-Ⅱ(Angiotensin-Ⅱ,Ang-Ⅱ)的水平。结果:与假手术组比模型组大鼠CTGF mRNA的表达显著上调(P<0.01),Ang-Ⅱ的水平升高(P<0.05)。与模型组比塞来昔布5 mg-1·kg-1·d-1和10mg-1·kg-1·d-1治疗组能显著降低CTGF mRNA的表达,Ang-Ⅱ水平无改变。但塞来昔布30 mg-1·kg-1·d-1治疗组与模型组比Ang-Ⅱ的水平升高(P<0.05)。结论:环氧合酶-2抑制剂对肾脏的保护作用与剂量密切相关,小剂量应用可延缓肾间质纤维化的发生,大剂量应用可能通过升高Ang-Ⅱ的水平而产生对肾脏的不利影响。

Effects of Different Doses of Cyclooxygenase-2 Inhibitor on Renal Tubulointerstitial Fibrosis in Rats with Obstructive Nephropathy

Objective To evaluate the effect of different doses of celecoxib on renal tubulointerstitial fibrosis in rats with obstructive nephropathy and to investigate its possible mechanism.Methods The unilateral ureteral obstruction(UUO) models were prepared by ligating the left ureter of rats.Treatment groups were given celecoxib with a dose of 5 mg·kg-1·d-1,10 mg·kg-1·d-1,30 mg·kg-1·d-1by intragastric administration from 1 d before obstruction to 7 d after the induction,respectively.The rats in model and sham groups were given the same volume 0.9% sodium chloride solution by intragastric administration as control.The mRNA expression of CTGF was determined by RT-PCR,the expression of CTGF,α-SMA,FN protein was examined by immunohistochemical stain,the plasma content of Ang-Ⅱ was determined with radioimmuno assay(RIA).Results Compared with sham group,the expression of CTGF mRNA and level of Ang-Ⅱ was significantly increased in model group(P < 0.01,P < 0.05).Compared with model group,the expressions of CTGF mRNA was down-regulated,the levels of Ang-Ⅱ had no change in celecoxib 5 mg·kg-1·d-1and 10 mg·kg-1·d-1groups,meanwhile the level of AngⅡ was significantly increased in celecoxib 30 mg·kg-1·d-1group(P < 0.05).Conclusion The protective effects of cyclooxygenase-2 inhibitor celecoxib on kidney was closely related with dosage,the use of a lower dose could delay the development of renal tubulointerstitial fibrosis,but a higher does of celecoxib may aggravate the injure of kidney through up-regulating the Ang-Ⅱ level.