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目的观察白藜芦醇联合厄贝沙坦对单侧输尿管梗阻(unilateral ureteral obstruction,UUO)大鼠肾间质纤维化的影响并探讨其可能机制。方法制备UUO肾间质纤维化大鼠模型,将40只大鼠随机分为5组,即假手术组、模型组、白藜芦醇组、厄贝沙坦组以及白藜芦醇和厄贝沙坦联合组,每组8只。术后2周处死大鼠,过碘酸-Schiff染色和脂氢过氧化病理分析肾间质纤维化指数,并应用免疫组织化学方法检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA),用Western Blot分析α-SMA、fibronectin、p-Smad3、p NF-κBp65、ICAM-1、TNF-α,用ELISA检测过氧化物酶体增殖剂激活受体(peroxisome proliferators-activated receptors,PPARs)、转化生长因子β1(transforming growth factor-β1,TGF-β1)、巨噬细胞炎症蛋白2(marcophage inflammatory protein-2,MIP-2)和单核细胞趋化因子1(monocyte chemtaticprotein-1,MCP-1)。结果过碘酸-Schiff染色和脂氢过氧化结果显示模型组肾小管损伤面积远大于其它各组。免疫组化分析模型组中α-SMA的表达高于其它各组,联合治疗组α-SMA的表达在治疗组中表达较少,但高于假手术组。模型组大鼠肾间质α-SMA、fibronectin、p-Smad3、p NF-κBp65、ICAM-1、TNF-α的表达增多,联合治疗组较厄贝沙坦和白藜芦醇组的表达减少(P<0.05),但厄贝沙坦和白藜芦醇组之间差异无统计学意义(P>0.05)。模型组TGF-β1、MIP-2和MCP-1的水平高于其它各组,在治疗组中,联合治疗组这些细胞因子的水平低于另外2组。与模型组比较,其它组PPAR(α、β和γ)酶活性增加(P<0.05)。结论白藜芦醇和厄贝沙坦可抑制NF-κB、TGF-β1等途径减缓肾纤维化的病程进展,且联合治疗对肾纤维化的减缓更显著。
Objective To observe the effect of resveratrol combined with irbesartan on renal interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) and to explore its possible mechanism. Methods UUO renal interstitial fibrosis rat model was prepared, 40 rats were randomly divided into 5 groups, namely sham operation group, model group, resveratrol group, irbesartan group and resveratrol and irbesa Tan combined group, each group of eight. The rats were sacrificed 2 weeks after operation, and the index of renal interstitial fibrosis was analyzed by periodic acid-Schiff staining and lipoperoxidation. The expressions of α-smooth muscle actin (α- SMA). The expressions of α-SMA, fibronectin, p-Smad3, NF-κBp65, ICAM-1 and TNF-α were detected by Western Blot. Peroxisome proliferators- activated receptors PPARs, MIP-2, monocyte chemtatic protein-1 MCP-1). Results The periodic acid-Schiff staining and lipoperoxidation showed that the area of renal tubular injury in model group was much larger than that in other groups. The expression of α-SMA in the model group was higher than that in other groups. The expression of α-SMA in the combination group was less in the treatment group than in the sham operation group. The expression of α-SMA, fibronectin, p-Smad3, p-NF-κBp65, ICAM-1 and TNF-α in renal interstitium increased in model group compared with that in irbesartan and resveratrol (P <0.05), but there was no significant difference between irbesartan and resveratrol groups (P> 0.05). The levels of TGF-β1, MIP-2 and MCP-1 in the model group were higher than those in other groups. In the treatment group, the levels of these cytokines in the combination therapy group were lower than the other two groups. Compared with the model group, the other groups PPAR (α, β and γ) enzyme activity increased (P <0.05). Conclusion Resveratrol and irbesartan can inhibit the progression of renal fibrosis by inhibiting NF-κB, TGF-β1 and other pathways, and the combination therapy has a more significant slowdown of renal fibrosis.