阿利吉仑对高血压肾病小鼠肾的保护作用及其作用机制

Effects and mechanism of aliskiren on phosphatidyl inositol 3-kinase/protein kinase B signaling pathway and Caspase-3 expression in mice with hypertensive nephropathy

目的探究阿利吉仑对高血压肾病小鼠的保护作用及其对磷脂酰肌醇激/蛋白激酶B(PI3K/Akt)信号通路和半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)表达的影响。方法用微渗泵灌注血管紧张素Ⅱ制备高血压小鼠肾病模型。按照体重将小鼠随机分为6组:假手术组、模型组和低、中、高3个剂量实验组(灌胃阿利吉仑12. 5,25. 0,50. 0 mg·kg^(-1))与对照组(卡托普利30 mg·kg^(-1)),每组15只;造模后给药,每日1次,连续灌胃2周。以实时定量PCR法测定肾组织中胰岛素受体底物2(Irs2)、磷脂酰肌醇激酶-3(PI3K)、蛋白激酶B(Akt) mRNA表达;以免疫印迹法测定Irs2、PI3K、Akt与Caspase-3蛋白表达情况。结果给药4周,假手术组、模型组、对照组和高剂量实验组的PI3K mRNA表达分别为1. 14±0. 21,0. 34±0. 08,1. 07±0. 23和0. 96±0. 22;这4组的Akt mRNA表达分别为1. 23±0. 27,0. 45±0. 13,1. 05±0. 16和0. 91±0. 15,模型组与假手术组比较或高剂量实验组与模型组比较,差异均有统计学意义(均P <0. 05)。这4组的小鼠肾组织Caspase-3蛋白表达水平分别为0. 29±0. 06,1. 06±0. 13,0. 31±0. 06和0. 37±0. 08,模型组与假手术组比较或高剂量实验组与模型组比较,差异均有统计学意义(均P <0. 05)。结论阿利吉仑对高血压小鼠肾具有一定的保护作用,其机制可能与激活PI3K/Akt信号通路、抑制Caspase-3表达有关。

Objective To explore the protective effect of aliskiren on hypertensive nephropathy mice and its influences on the expressions of phosphatidyl inositol 3-kinase / protein kinase B (PI3K/Akt) signaling pathway and cysteine aspartate proteinase-3 (Caspase-3) .Methods Preparation of hypertensive nephropathy model was performed by infusion of angiotensin Ⅱ with micro osmotic pump.Mice were divided into 6 groups(n = 15 in each group) : sham operation group,model group,experimental low,medium and high dose groups (12.5,25.0,50.0 mg·kg^-1 aliskiren) and control group (30 mg·kg^-1 captopril) ,once a day,gavage administration for 2 weeks.Expressions of insulin receptor substrate 2(Irs2) ,phosphatidyl inositol 3-kinase(PI3K) and protein kinase B(Akt) mRNA were determined by real-time quantitative PCR.The expressions of Irs2,PI3K,Akt and Caspase-3 proteins were determined by Western blot.Results After 4 weeks of administration,the PI3K mRNA of mice in sham operation group,model group,control group and high-dose experimental group were 1.14±0.21,0.34±0.08,1.07±0.23,0.96±0.22; the Akt mRNA in the 4 groups were 1.23±0.27,0.45±0.13,1.05±0.16,0.91±0.15,comparison between model group and sham operation group,or high dose experimental group and model group,the differences had significant (all P<0.05) .The Caspase-3 protein in the 4 groups were 0.29±0.06,1.06±0.13,0.31±0.06,0.37±0.08,comparison between model group and sham operation group,or high dose experimental group and model group,the differences had significant (all P<0.05) . Conclusion Aliskiren had a protective effect on the kidneys of hypertensive mice,its mechanism may be associated with the activation of the PI3K/Akt signaling pathway,and the inhibition of Caspase-3 expression.