幼鼠肾小管间质损伤不同时期缺氧诱导因子-1α的表达趋势及意义

The expression and significance of hypoxia inducible factor-1α at tubulointerstitial lesions in kidney from unilateral uteral obstraction young rats

目的探讨单侧输尿管结扎模型(UUO)幼年大鼠肾间质损伤过程中缺氧诱导因子-1α(HIF-1α)、转化生长因子-β1(TGF-β1)组织定位表达的趋势、相关性及潜在的病理意义,以及用苯那普利和氯沙坦联合治疗的效应。方法采用单侧输尿管结扎的方法制备实验性幼鼠梗阻性肾小管间质损伤模型,第3、7、14、28天作为观察点,用Masson染色评价各组各时间点肾小管间质损伤程度,免疫组织化学法分别检测各组幼鼠肾组织HIF-1α和TGF-β1定位、表达趋势及相关性。结果UUO模型组HIF-1α、TGF-β1蛋白表达及肾小管间质损伤的程度均明显高于假手术组(P<0.05);HIF-1α与TGF-β1均在持续了约14d左右的高表达后随纤维化的加重其表达反而有所下降;而在治疗组各指标的表达明显低于UUO模型组(P均<0.01),但各时间点比较其表达仍强于假手术组(P均<0.05);HIF-1α、TGF-β1及肾小管间质损伤指数之间呈正相关;治疗组各指标的表达水平明显低于UUO模型组(P<0.05)。结论在幼年大鼠肾小管间质损伤过程中,HIF-1α、TGF-β1的表达上调具有重要的致病意义,而苯那普利和氯沙坦治疗具有明显的干预效应。

Objective To observe the trend, relevance and potential pathogentic significance of hypoxia inducible factor-1α（HIF-1α） and transforming growth factor-β1（TGF-β1） during tubulointerstitial injury in kidneys of young rats with unilateral ureterat obstraction （UUO）, and the intervention effects of combined therapy with benazepril and losartan. Methods Young Wistar male rats with UUO were used as experiment models. At the days 3, 7, 14 and 28, we evaluated the degree of tubulointerstitial injury of the three groups by Masson staining, and detected the expression, localization of HIF-1α, TGF-β1, and correlation among them in the obstructed kidneys by immunohistochemistry staining. Results In the UUO group, expression of HIF-1α and TGF-β1 were much more intensive and the degree of tubulointerstitial injury much higher than as found in the sham operation group （P〈0.05）. The expressions of HIF-1α and TGF-β1 peaked at days 7 through 14, and gradually declined at days 21 through 28 as fibrosis became deteriorated. The expression of HIF-1α, TGF-β1 were consistent with the damage of tubulointerstitial injury. The positive correlation among HIF-1α, TGF-β1 and the tubulointerstitial injury scores were significant. At all time spots, the rats on treatment presented with levels of HIF-1α and TGF-β1 expression that were much lower compared with the untreated UUO rats yet higher compared with sham operated rats. Conclusion In the course of tubulointerstitial lesions with young rats, the up-regulated expression of HIF-1α,TGF-β1 exhibit significant pathogenic effect, while the benazepril and losartan treatment may have an important role for intervention.