环氧化酶-2抑制剂对糖尿病大鼠肾脏活性作用的研究

Renal protective Effects of Rofecoxib on Early Streptozotocin-induced Diabetic Rats

目的观察糖尿病大鼠肾脏的环氧化酶-2(cyclooxygenase-2,COX-2)的表达,并探讨COX-2抑制剂罗非昔布(rofe-coxib)对早期糖尿病肾病的活性作用。方法实验大鼠随机分为正常对照组(C组)、糖尿病组(D组)及糖尿病rofecoxib治疗组(DL组)。各组分别于模型建立后第1、3、6周留取24h尿液,第3、6周末留取血液和肾组织,放免法测定尿6-酮前列腺素F1a(6-Ket-PGF1a)、尿血栓素B2(TXB2)、24h尿白蛋白及血清、尿液的胰岛素样生长因子-I(IGF-I);用考马斯亮蓝法测定24h尿总蛋白:ELISA法测定血清、尿液转化生长因子-β1(TGF-β1);免疫组织化学染色法观察肾脏COX-2的表达。结果D组肾脏肥大指数、COX-2表达、尿白蛋白(uAlb)、24h总蛋白(uPro)、TGF-β1、IGF-I均较C组明显升高(P<0.01);DL组上述指标低于D组(24h总蛋白和肥大指数P<0.05,其余P<0.01)。D组尿6-Ket-PGF1a在3、6周末较C组降低(P<0.01),尿TXB2在6周末较C组升高(P<0.01);DL组两项指标均较糖尿病组降低(前者P<0.01,后者P<0.05)。结论糖尿病大鼠肾脏的COX-2表达增加,rofecoxib可以通过抑制COX-2,影响前列腺素代谢,降低尿蛋白,从而减轻早期糖尿病肾脏损害。

Objective To observe the expression of cyclooxygenase-2 （COX-2） in the kidney of STZ-indueed diabetic rats, and to further study how the COX-2 inhibitor, rofecoxib,influence the prostaglandin metabolism,renal structure and function in early diabetic nephropathy. Methods The following groups were studied：normal control rats,streptozotocin diabetic rats and diabetic rats treated with rofecoxib （50mg/kg·d）. 6 rats were killed in each group at the 3rd and 6th weekend after the diabetic model was successfully induced. The expression of COX-2 was determined by immunohistochemical staining. Radioimmunitical method were used to quantitate level of 6-Ket- PGF1 a,TXB2, albumin in urine, and IGF-I in both urine and serum. The concentration of TGF-β1 in urine and serum was measured by enzyme linked immune assay. Also,24-hour urine protein was measured by biochemical method. Results Kidney hypertrophy index,renal COX-2 expression,urine albumin,24-hour urine protein,TCF-β1 and IGF-Ⅰ greatly increased in diabetic rats（P〈0.01）, while rofecoxib inhibit above indexes obviously （P〈0.01 or P〈0.05）. Urine level of 6-Ket-PGF1 a decreased in diabetic rats （P〈0.01） and TXB2 increased in the 6th weekend in diabetic rats（P〈0.01） , but both of them reduced significantly in the group treated with rofecoxib（P〈0.01 or P〈0.05）. Conclusion Rofecoxib, a specific inhibitor of COX-2, depressed the higher expression of COX-2 in the kidneys of STZ-induced diabetic rats, also reduced the urine protein and pathologic prostaglandin generation, which can alleviate the early renal structure and function disorders in diabetic nephropathy rats.