选择性环氧化酶2抑制剂抑制尿毒症大鼠甲状旁腺异常增生  

Effects of selective cyclooxygenase 2 inhibitor on the hyperplasia of parathyroid glands from uremic rats

作　　者：邱君思[1] 张倩[1] 卢燕雯[1] 李屾森[1] 李海明[1] 尤莉[1] 顾勇[1] 郝传明[1] 陈靖[1] 

机构地区：[1]复旦大学附属华山医院肾脏科复旦大学肾脏病研究所,上海200040

出　　处：《中华肾脏病杂志》2012年第2期127-132,共6页Chinese Journal of Nephrology

基　　金：基金项目：国家自然科学基金（30971373）;上海市卫生局科研课题（2007123）;南京医科大学面上项目（NJMU002）

摘　　要：目的 评价环氧化酶2（COX2）抑制剂塞来昔布（celecoxib）对尿毒症大鼠甲状旁腺（PG）异常增生的影响.方法 通过5/6肾大部分切除结合高磷饮食（P 1.2％,Ca 1.2％）建立尿毒症甲状旁腺功能亢进症（甲旁亢）大鼠模型,存活大鼠按随机数字表法分成尿毒症甲旁亢非用药组（Nx-HP组,n=17）、塞来昔布预防组（Prey组,n=18,建模后1d起给塞来昔布100 mg· kg-1· d-1）和塞来昔布治疗组（Ther组,n=18,建模1个月后给塞来昔布100 mg·kg-1·d-1）,并以假手术组作为对照（Sham组,n=14）.12周后检测各组大鼠肾功能、血甲状旁腺激素（iPTH）水平、PG大小以及PG中增殖细胞核抗原（PCNA）、COX2表达.结果 Nx-HP组大鼠血清iPTH水平较Sham组显著升高[（100.73±4.35） ng/L比（34.77±0.83） ng/L,P＜0.01],塞来昔布干预后iPTH水平显著下降[Prev组（87.36±2.18） ng/L,Ther组（87.47±1.76） ng/L]（均P＜ 0.05）.计算显微镜下PG最大面积显示,Nx-HP大鼠PG最大面积显著增大,是Sham组的5.28倍[（2.436±0.372） mm2/kg比（0.461±0.089） mm2/kg,P＜0.01]；而Prey组[（0.987±0.254）mm2/kg]和Ther组[（1.270±0.305） mm2/kg]PG分别缩小59.47％（P＜0.01）和47.87％ （P＜0.05）,两组间差异无统计学意义.PCNA在Sham组PG中仅少量表达,Nx-HP组显著增多,塞来昔布干预后PCNA阳性细胞明显减少,Prey组和Ther组蛋白表达水平分别降低52.91％和34.68％（均P＜0.05）.COX2在Sham组PG中几乎未见表达,但在尿毒症大鼠中明显增多,Nx-HP组、Prey组和Ther组分别为Sham组的2.47倍、2.34倍和3.04倍（均P＜0.05）,而3组间差异无统计学意义.实时定量PCR检测PCNA和COX2基因水平显示同样变化趋势.结论 选择性COX2抑制剂塞来昔布可以显著抑制尿毒症大鼠甲旁亢和甲状旁腺增生.Objective To investigate the effects of selective cyclooxygenase 2 inhibitor on the hyperplasia of parathyroid glands from uremic rats. Methods Sixty-five 5/6-nephrectomized （Nx） and fifteen sham operated rats were assigned to 4 groups： （1）Sham group （n=14）：shamoperated ＋normal phosphate diet （P 0.8%,Ca 1.2%）; （2） Nx-HP group （n=17）：Nx＋high phosphate（HP） diet （P 1.2%,Ca 1.2%）; （3）Prophylactic COX2 inhibition group （Prey group,n=18）：Nx＋HP＋celecoxib 100 mg· kg-1·d-1 for 3 months; （4）Therapeutic group （Ther group,n=18）：Nx＋HP＋celecoxib 100 mg·kg-1·d-1 starting at the second month of the 5/6 nephrectomy.At the end of 3 month,blood,urine and parathyroid samples were collected.The expressions of COX2 and PCNA were determined by immunohistochemistry,Western blotting and real-time PCR. Results All of the Nx rats fed with high phosphate diet for 3 months manifested progressively increasing serum creatinine,serum iPTH as well as augmentation of parathyroid gland volume,suggesting that secondary parathyroid hyperplasia animal model was established successfully.Celecoxib significantly decreased serum iPTH levels [Sham （34.77±0.83）,Nx-HP（100.73±4.35）,Prey （87.36±2.18）,Ther （87.47±1.76） ng/L,P〈0.05],the size of the parathyroid glands in Nx rats [Sham （0.461±0.089）,Nx-HP （2.436±0.372）,Prey （0.987±0.254）,Ther （1.27±0.305） mm2/kg,P〈0.05] and PCNA expression in PG determined by Western blotting （decreased to 52.91% in Prev group and 34.68% in Ther group respectively,P〈0.05）.No significant difference was observed between the two COX2 inhibition groups.The levels of COX2 expression in parathyroid gland were greatly increased in three Nx groups compared with that in sham group （2.47-fold in Nx-HP,2.34-fold in Prey group,3.04-fold in Ther group,P〈0.05）.COX2 inhibitor had no effects on COX2 expression in PGs.Real-time PCR analysis demonstrated the same trends of mRNA expression of COX2 and PCNA in PGs of rats

关 键 词：尿毒症 甲状旁腺 环氧化酶2抑制剂 增殖细胞核抗原 

分 类 号：R692.5[医药卫生—泌尿科学]