阿利吉仑对2型糖尿病db/db小鼠肾脏损伤的保护作用

目的 观察肾素抑制剂阿利吉仑对2型糖尿病db/db小鼠肾脏损伤的保护作用。 方法 8周龄db/db和db/m小鼠行单侧肾切除，16周进入实验，分为4组：db/m小鼠对照组（db/m组）、db/db糖尿病小鼠对照组（db/db组）、db/db糖尿病小鼠阿利吉仑3 mg&#8226;kg-1&#8226;d-1治疗组（db/db+A3组）和db/db糖尿病小鼠阿利吉仑25 mg&#8226;kg-1&#8226;d-1治疗组(db/db+A25组)。阿利吉仑溶于磷酸盐缓冲液（PBS，350 mg/L）皮下泵入（0.25 μl/h）给药，疗程４周。治疗前后检测体质量、血糖、糖化血红蛋白、尿蛋白量、血压水平；PAS染色观察肾脏组织学变化；ELISA法检测肾皮质转化生长因子β1（TGF-β1）和纤溶酶原激活抑制因子1（PAI-1）含量；间接免疫荧光检测肾小球Ⅳ型胶原（ColⅣ）和纤连蛋白（FN）表达；实时定量PCR检测TGF-β1、PAI-1、ColⅣ、FN和肾素mRNA表达；放射免疫法检测肾皮质肾素活性和血管紧张素Ⅱ（AngⅡ）水平。 结果 与db/m组小鼠比较，db/db组小鼠有大量蛋白尿，肾小球细胞外基质沉积增加，TGF-β1、PAI-1、ColⅣ和FN蛋白及mRNA表达增加，同时肾皮质肾素mRNA、肾素活性和AngⅡ水平增高（均P < 0.05）。阿利吉仑25 mg&#8226;kg-1&#8226;d-1治疗在没有影响血压情况下，显著减少db/db小鼠24 h尿蛋白量，减少肾小球细胞外基质沉积，减少TGF-β1、PAI-1、ColⅣ、FN蛋白和mRNA表达，同时降低肾皮质肾素活性和AngⅡ水平（均P < 0.05）。 结论 阿利吉仑对2型糖尿病db/db小鼠肾脏损伤有保护作用。

Protective effect of aliskiren on type 2 diabetic nephropathy in db/db mice

Objective To investigate the effect of aliskiren on type 2 diabetic nephropathy in db/db mice.Methods Eight-week old db/db and db/m mice were subjected to right nephrectomy to hasten the development of diabetic nephropathy.At age of 16 weeks,they were divided into four groups:db/m group (normal control),db/db group ( diabetic control),db/db+ A3 group (db/db mice treated with aliskiren 3 mg·kg-1"d-1) and db/db+A25 group (db/db mice treated with aliskiren 25 mg "kg-1 "d-1).Body weight,blood glucose,glycosylated hemoglobin,proteinuria and systolic blood pressure were measured before and after treatment.After treatment,renal histological examination by PAS staining,TGF-β1 and PAI-1 protein by ELISA,expression of ColⅣ and FN protein by immunofluorescence,mRNA expression of TGF-β1,PAI-1,ColⅣ,FN and renin by real time PCR,renin activity and angiotensin Ⅱ level by radioimmunoassay were performed.Results Treatment for 4 weeks of aliskiren at a dose of 25 mg" kg-1" d-1 markedly decreased urinary albumin excretion,glomerulosclerosis and suppressed synthesis of TGF-β1,PAI-1,Col Ⅳ,FN without inducing significantl change in systolic blood pressure,compared to those of db/db group (all P＜0.05).Aliskiren also suppressed renin activity and angiotensin Ⅱ level in renal cortex (all P＜0.05).Conclusion Aliskiren protects against type 2 diabetic nephropathy.