伊贝沙坦联合舒洛地特对糖尿病大鼠肾脏协同保护作用的研究

目的： 探讨伊贝沙坦联合舒洛地特对大鼠糖尿病肾脏协同保护作用及其机制。 方法：将雄性SD大鼠随机分为5组:正常对照组（C）、糖尿病模型组(D)、伊贝沙坦组(I)、舒洛地特组（S）及伊贝沙坦与舒洛地特联合给药组（I+S），糖尿病大鼠模型用STZ诱导。 12周后观察尿白蛋白的排泄率(UAER)，做肾组织病理检查，测定肾组织中MDA含量与SOD、CAT、GSH-PX的活性变化。RT-PCR法检测肾组织中ICAM-1 mRNA的表达。EMSA 检测NF-κB的活性。结果：各给药组均可抑制糖尿病大鼠UAER的增加及肾组织病理结构损害，联合组优于单独给药组。对肾组织MDA含量增加及抗氧化应激的SOD、CAT、GSH-PX活性降低的改善作用，联合组优于单给药组。各给药组均可抑制肾组织NF-κB活性，以联合组最明显；糖尿病大鼠肾组织ICAM-1 mRNA表达明显高于对照组，各给药组肾组织ICAM-1 mRNA表达明显低于模型组，其中以联合组最明显。 结论：伊贝沙坦与舒洛地特联合用药对糖尿病肾脏保护作用优于任一单种用药,其机制可能部分是通过对糖尿病肾组织氧化应激、NF-κB 活性及 ICAM-1 mRNA表达协同抑制而实现的。

Renal protection of combination of irbesartan and sulodexide on diabetic rat

AIM: To assess renal protective effects of the combination of irbesartan and sulodexide on STZ-induced diabetic rats. METHODS: Diabetes was induced by injection of streptozotocin in rats. The animals were randomly divided into five groups: control (C), diabetes (D), diabetes treated with irbesartan (I), diabetes treated with sulodexide (S), and diabetes treated with combination of irbesartan and sulodexide (I+S). Urine albumin excretion rate (UAER), the level of malondialdehyde (MDA) and activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in renal tissues were determined, and renal tissue morphology was observed under light microscope after 12 weeks. Expression of ICAM-1 mRNA was examined by RT-PCR. NF-κB was evaluated using electrophoretic mobility shift assay (EMSA). RESULTS: Increased UAER and kidney pathologic injury were attenuated by treatment with either irbesartan or sulodexide alone and further reduced by using the combination of the two drugs. Elevated MDA level and decreased activities of SOD, CAT and GSH-PX in diabetic renal tissues were improved by irbesartan or sulodexide, and more effectively by combination of irbesartan and sulodexide. NF-κB activities were higher in renal tissue of diabetic rats than those in control group, and further abrogated by combination therapy in both cases (P<0.05). Over-expression of ICAM-1 mRNA observed in diabetic rats was attenuated by irbesartan or sulodexide to a similar level and further reduced by the combination of two drugs(P<0.05). CONCLUSION: The combination of irbesartan and sulodexide confers superiority over mono-therapies on the effect of renal protection. The mechanism may be at least partly correlated with synergestic suppression of increasing oxidative stress and NF-κB activities as well as over-expression of ICAM-1 mRNA in renal tissues.