血管紧张素转移酶2(ACE2)在糖尿病致大鼠肝脏氧化应激损伤中的作用及机制分析

Protective Effect and Mechanism of Angiotensin Converting Enzyme 2(ACE2) against Diabetes-Induced Liver Oxidative Stress Injury in Rats

目的:探讨血管紧张素转移酶2(ACE2)在糖尿病致大鼠肝脏氧化应激损伤中的作用和可能机制。方法:24只健康雄性SD大鼠,随机选取8只作为正常对照组,剩余16只按60mg/kg(以体质量计)一次性腹腔注射STZ溶液制备糖尿病肝脏氧化应激损伤模型,成模后大鼠随机分为2组:糖尿病组和胰岛素治疗组(优泌林3.7×10-8mol/d),30d后宰杀,取血液和肝脏组织等进行各指标测定:1)测定血清中AGEs含量;2)测定肝脏组织中过氧化氢(H2O2)、丙二醛(MDA)的含量及过氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)的活力;3)肝脏组织中血管紧张素Ⅱ(AngⅡ)、血管紧张素1-7(Ang1-7)的含量,ACE和ACE2酶活力的测定。结果:1)正常对照组大鼠空腹血糖均值为(5.39±0.30)mmol/L,糖尿病组大鼠空腹血糖均值持续维持在(28.24±2.51)mmol/L(远高于高水平高血糖状态指标值16.6mmol/L),胰岛素治疗后大鼠空腹血糖水平明显下降至(11.18±1.26)mmol/L,显著高于正常对照组(P<0.05),但同时显著低于糖尿病组(P<0.05),且治疗后期已经低于10.0mmol/L并逐渐接近正常对照组。糖尿病组大鼠血清中的AGEs的含量显著高于正常对照组和胰岛素治疗组(P<0.05)。2)与正常对照组和胰岛素治疗组相比,糖尿病组大鼠肝脏组织中的MDA和H2O2极显著增多(P<0.01),SOD和GSH-Px的活力极显著降低(P<0.01);AngⅡ的含量显著增多(P<0.01),Ang1-7含量显著降低(P<0.01),ACE的酶活力显著升高(P<0.01),而ACE2的酶活力显著降低(P<0.01)。结论:糖尿病时大鼠肝脏组织局部AngⅡ显著升高,ACE2活力下降,肝脏组织处于氧化应激状态。胰岛素治疗后,ACE2活力增高,致AngⅡ降解,AngⅡ含量显著降低,肝脏的氧化应激减缓,提示ACE2对糖尿病大鼠肝脏氧化应激损伤有一定的保护作用,其机理可能与对AngⅡ降解作用增强有关。

This study aimed to investigate possible protective effect and mechanism of ACE2 against diabetes-induced liver oxidative stress injury in rats. A total of 24 male healthy SD rats were used in this study. Eight rats without any treatment were used as negative control, and 16 others were administrated with STZ solution （60 mg/kg） via the ip route to induce diabetic hepatic oxidative stress injury model and then divided into 2 groups： diabetes group and insulin （3.7 × 10-8 mol/d） treatment group. After 30 days of administration, all the rats were sacrificed and blood and hepatic tissues were harvested to measure the content of AGEs in serum, the contents of MDA, H2O2 and the activity of SOD and GSH-Px in hepatic tissues. The contents of AngⅡ and Ang1-7 were also investigated as well as the activities of ACE and ACE2 in hepatic tissues. Results showed that the average fasting blood glucose level in normal control group was （5.39 ± 0.30） mmol/L, compared to （28.24 ± 2.51） mmol/L （much higher than the hyperglycemia index of 16.6 mmol/L） in diabetes group. The average fasting blood glucose level of measurements at intervals of 5 days during the administration period was significantly reduced to （11.18 ± 1.26） mmol/L, which, however, was still significantly higher than normal control group （P 〈 0.05）, and reached a level lower than 10.0 mmol/L and even close to the normal level at the end of the administration period. The serum content of AGEs in diabetes control group was significantly higher than that in normal control group and insulin treatment group （P 〈 0.05）. Compared with normal control group and insulin treatment group, there were significant increases in the serum content of AngⅡ, the activity of ACE and the contents of MDA and H2O2 in hepatic tissues of diabetes group but reductions in the activities of SOD, GSH-Px and ACE2 and the content of Ang1-7. In summary, the liver of the diabetes rats had a local increase in AngⅡ content but a decrease in ACE2 content and underwent oxidative stress. Following insulin treatment, the enhancement in ACE2 activity resulted in degradation of AngⅡ, thus relieving the oxidative stress of liver. These results suggest that ACE2 might have some protective effect against hepatic oxidative stress in diabetes rats and the mechanism appears to be related to the enhanced degradation of AngⅡ.