血管生成素1改善糖尿病大鼠肾脏缺氧状态的研究  

Angiopoietin-1 improves renal hypoxia in diabetic rats

作　　者：胡琳弘 陈文佳 白冰[1] 杨亦彬[1] HU Linhong;CHEN Wengjia;BAI Bing(Department of Nephropathy Rheumatology,Zunyi Medical College Affiliated Hospital,Zunyi 563003,China)

机构地区：[1]遵义医学院附属医院肾病风湿科

出　　处：《中国糖尿病杂志》2019年第11期842-851,共10页Chinese Journal of Diabetes

基　　金：国家自然科学基金（81260118）;遵义医学院博士科研启动基金[（2006）13]

摘　　要：目的探讨血管生成素1(Ang-1)对糖尿病大鼠肾脏缺氧相关指标的影响。方法STZ腹腔注射建立糖尿病大鼠模型,随机分为正常对照(NC)组、糖尿病(DM)组、糖尿病Ang-1干预(AV)组及糖尿病空腺病毒(BV)组。AV组成模8周后单次注射Ad-Ang-1(3×10~8pfu/只),BV组成模8周后单次注射空白腺病毒载体(3×10~8pfu/只)。各组于12、16周末检测血糖、24 h尿蛋白(24 h UP)及肾皮质中低氧诱导因子1α(HIF-1α)、血红素加氧酶1(HO-1)、脯氨酸羟化酶2(PHD2)的蛋白及基因水平,通过缺氧探针观察肾脏缺氧情况。结果与NC组比较,DM、AV、BV组血糖、24 h UP升高(P<0. 01),肾组织出现DKD病理改变,缺氧阳性染色范围扩大。AV组肾脏缺氧阳性染色面积低于DM组(P<0. 01)。DM、BV组HIF-1α、HO-1、PHD2的积分光密度值(IOD)高于NC组(P<0. 05);AV组HIF-1α、HO-1的IOD值高于DM、BV组(P<0. 05),PHD2的IOD值低于DM、BV组(P<0. 05)。DM、AV、BV组HIF-1α、HO-1蛋白表达较NC组升高(P<0. 05)。AV组HIF-1α、HO-112周时蛋白表达高于DM、BV组(P<0. 05)。DM、BV组PHD2蛋白表达较NC组升高(P<0. 05)。AV组16周PHD2蛋白表达低于BV组(P<0. 05)。DM、AV、BV组HIF-1α、HO-1蛋白在16周表达较12周降低(P<0. 05)。AV组HIF-1αmRNA表达较NC组升高(P<0. 05),AV组16周时HO-1mRNA表达均较NC组升高(P<0. 05)。DM、BV组PHD2 mRNA表达较NC组升高(P<0. 05)。结论糖尿病大鼠肾脏存在慢性缺氧,Ang-1可改善糖尿病大鼠肾脏缺氧状态,其机制可能与上调HIF-1α及HO-1表达、抑制PHD2表达相关。Objective To investigate the effects of Ang-1 on renal hypoxia.MethodsSD rat diabetic model was constructed by intraperitoneal injection with streptozotocin. Then all the rats were randomly divided into four groups:normal control group(NC group),diabetic group(DM group),Ang-1 treatment group(AV group),and blank vector group(BV group). Eight weeks after the diabetic model was constructed,AV group was treated with Ad-Ang-1 injection(3×108 pfu/rat),while BV group was treated with blank vector injection(3×108 pfu/rat). Blood glucose,24 h urinary protein(24 h UP),the protein and m RNA of hypoxia-inducible factor-1α(HIF-1α),heme oxygenase-1(HO-1),and prolyl hydroxylase2(PHD2)were tested at the end of 12 and 16 weeks. Hypoxic status in renal tissue was detected by HypoxyprobeTM-1 immunohistochemistry.ResultsThe blood glucose and 24 h UP were higher in DM,AV,and BV group than in NC group(P<0. 01). The renal tissue in DM,AV and BV group showed obvious pathological changes of DKD,and the range of hypoxia positive staining was enlarged. The area of renal hypoxia positive staining was lower in AV group than in DM group(P<0. 01). The values of HIF-1α,HO-1,and PHD2 IOD were higher in DM and BV group than in NC group(P<0. 05). The values of HIF-1α and HO-1 IOD were higher,and the values of PHD2 IOD was lower in AV group than in DM and BV group(P<0. 05). The expression of HIF-1α,HO-1 protein and were significantly higher in DM,AV and BV group than in NC group(P<0. 05). The expression of HIF-1α,HO-1 protein were significantly higher in AV group than in DM and BV group(P<0. 05). The expression of PHD2 protein was significantly higher in DM and BV group than in NC group(P<0. 05). The expression of PHD2 protein was significantly lower in AV group than in BV group in 16 w(P<0. 05). The expression of HIF-1α and HO-1 protein in DM,AV and BV group were lower in 16 w than in 12 w(P<0. 05). The expression of HIF-1α m RNA was higher in AV group than in NC group(P<0. 05). The expression of HO-1 m RNA was higher in AV group than in

关 键 词：糖尿病肾脏疾病 缺氧 血管生成素1 低氧诱导因子1Α 

分 类 号：R73[医药卫生—肿瘤]