【作者】 杨绪枫；

【导师】 汪年松；

【作者基本信息】 苏州大学 ， 中西医结合临床， 2012， 硕士

【摘要】 目的观察舒洛地特对已应用ACEI和/或ARB类药物的2型糖尿病肾病患者的临床疗效及安全性。方法根据尿白蛋白排泄率将92例2型糖尿病肾病患者分为微量白蛋白尿组和大量白蛋白尿组，所有患者在入组前至少服用一种ACEI或ARB类降压药6个月，入组后在常规综合治疗的同时，前10天应用舒洛地特注射剂60mg/d静滴，后110天应用舒洛地特软胶囊100mg/d口服。用药前、用药4周、8周、12周及120天分别检测患者血压、空腹血糖、肝肾功能、凝血功能、24h尿蛋白定量等指标，并观察有无不良事件发生。结果微量白蛋白组和大量白蛋白组患者24h尿蛋白定量在治疗前分别为（0.62±0.13）g和（4.86±0.92）g，治疗12周后分别为（0.40±0.11）g和（3.02±0.73）g，治疗前后比较差异均有统计学意义（P<0.05）；治疗120天后两组患者24h尿蛋白定量分别为（0.36±0.12）g和（2.73±0.82）g，同治疗前比较分别下降（38.97±14.67）%和（41.32±18.24）%，两组患者下降率比较无统计学差异（P>0.05）。两组患者治疗前后血压、血糖、肝肾功能、凝血功能等指标均未见显著变化。治疗过程中所有患者均无严重不良反应发生。结论对已应用ACEI和/或ARB的伴有微量白蛋白尿或大量白蛋白尿的2型DN患者，舒洛地特能有效降低其尿蛋白，短期内对肝肾功能、凝血功能等指标无明显影响，临床应用安全。目的观察舒洛地特对糖尿病大鼠肾脏的保护作用并探讨其机制。方法采用STZ（链脲佐霉素，60mg/kg）腹腔注射法构建1型糖尿病大鼠模型，随机分为4组：DM组（糖尿病组）、S10组（舒洛地特10mg/kg/d组）、S20组（舒洛地特20mg/kg/d组）、L组（氯沙坦30mg/kg/d组），每组各10只。另取10只未造模大鼠作N组（正常对照组）。干预12周后采集各组大鼠血、尿标本和肾脏组织标本，观察和分析各组大鼠肾脏功能和结构的改变；Western blotting和免疫组织化学法检测肾组织VEGF、VEGF-R2、SOCS-1及TGF-β1蛋白的表达。结果同N组相比，DM组大鼠24h尿白蛋白定量、血肌酐及尿素氮显著增加（P<0.01），病理改变较明显。同DM组相比，治疗组（S10、S20及L组）大鼠24h尿白蛋白定量减少（P<0.05或P<0.01）；同S10组相比，S20及L组大鼠24h尿白蛋白定量减少（P<0.05）。光镜及电镜显示治疗组较DM组病理变化减轻，尤以S20及L组病变减轻明显。大鼠肾脏组织VEGF和VEGF-R2的表达，DM组明显高于N组（P<0.01），治疗组显著低于DM组（P<0.05或P<0.01）；SOCS-1的表达，DM组明显高于N组（P<0.05），治疗组显著高于DM组（P<0.05或P<0.01），而TGF-β1的表达，DM组明显高于N组（P<0.01），治疗组显著低于DM组（P<0.05或P<0.01）。结论舒洛地特对糖尿病大鼠肾脏有保护作用，而20mg/kg/d较10mg/kg/d的剂量效果更好。这种保护作用可能同下调肾脏组织VEGF和VEGF-R2蛋白表达，以及上调肾脏组织SOCS-1蛋白的表达，进而抑制TGF-β1蛋白的过表达有关。更多还原

【Abstract】 ObjectiveTo observe the efficacy and safety of sulodexide on patients of type2diabeticnephropathy who have received ACEI and/or ARB therapy.MethodsA total of92cases of type2diabetic nephropathy patients, who had received at leastone kind of ACEI and/or ARB drug therapy for at least6months, were devided into twogroups: the microalbuminuria group and the macroalbuminuria group. All the patients weregiven sulodexide60mg/d by intravenous infusion for10days, and then given sulodexide100mg/d by oral use for110days besides routine management. The blood pressure, fastingblood glucose, liver and kidney function, blood coagulation and24-hour urinary proteinwere measured before and4weeks,8weeks,12weeks and120days after the use ofsulodexide.ResultsThe24-hour urinary protein of the microalbuminuria group and the macroalbuminuriagroup were (0.62±0.13)g and (4.86±0.92)g before the treatment. And12weeks later, the24-hour urinary protein were （0.40±0.11）g and （3.02±0.73）g respectively. Thedifferences of the24-hour urinary protein before and after the treatment both of the groupswere significant（P<0.05）.120days of the treatment later, the24-hour urinary protein ofthe two groups were （0.36±0.12）g and （2.73±0.82）g, and reduced （38.97±14.67）%and （41.32±18.24）%respectively compared to those before the treatment. There wasno significant difference of the rate of the decline between the two groups（P>0.05）. There were no significant differences of the blood pressure, blood glucose, blood coagulation,liver and kidney function before and after the treatment both of the groups. There were noserious adverse events occurred during the treatment.ConclusionsSulodexide can effectively reduce urinary protein of type2DN patients withmicroalbuminuria or macroalbuminuria who have received ACEI and/or ARB therapy. Ithad no significant effect on the blood pressure, blood glucose, blood coagulation, liver andkidney function in short term. And it’s safe in clinical application. ObjectiveTo observe the renal protection of sulodexide in diabetic rats and to investigate themechanism.MethodsThe rat models of type1diabetes were established by intraperitoneal injection of STZ(streptozotocin,60mg/kg). Then the rats were randomly devided into four groups: DMgroup (diabetic model group), S10group (10mg/kg/d sulodexide group), S20group(20mg/kg/d sulodexide group), L group (losartan30mg/kg/d group),10rats per group.Another10normal rats were used as N group (normal control group). All the rats weretreated for12weaks. Then body weight,24-hour urinary albumin excretion, blood glucose(BG),serum creatinine(Scr), blood urea nitrogen(BUN) and kidney weight were measured;renal tissue samples were observed under optical and electron microscope. Expressions ofVEGF, VEGF receptor2(VEGF-R2), SOCS1and TGF-β1in renal tissue samples weredetected by Western blotting and immunohistochemistry.ResultsCompared with N group, DM group had significantly higher24-hour urinary albuminexcretion, Scr and BUN (P＜0.01), the pathological changes in the renal tissue samples inDM group were also obvious. Compared with DM group, the treated groups (S10, S20, and L group) had significantly lower24-hour urinary albumin excretion（P<0.05or P<0.01）,but there were no significant differences of Scr and BUN among the treated groups andDM group（P>0.05）. Compared with S10group, S20and L group had significantly lower24-hour urinary albumin excretion（P<0.05）. The pathological changes in the renal tissuesamples were much ameliorated in the treated groups, especially those in the S20and Lgroup. The expressions of VEGF and VEGF-R2in DM group were significantly higherthan those in N group （P<0.01）, and the expressions in the treated groups weresignificantly lower than that in DM group（P<0.05or P<0.01）. The expression of SOCS1in DM group was significantly higher than that in N group （P<0.05）, and the expressionin the treated groups was much higher than that in DM group （P<0.05or P<0.01）. Theexpression of TGF-β1in DM group was significantly higher than that in N group（P<0.01）,and the expression in the treated groups was significantly lower than that in DM group（P<0.05or P<0.01）.ConclusionsSulodexide has renal protective effect in diabetic rats, and20mg/kg/d is moreeffective than10mg/kg/d. The nephroprotective effect may be related to the regulating ofthe expressions of VEGF, VEGF-R2, SOCS1and TGF-β1in the renal tissues of diabeticrats.更多还原