带前导肽的人锰超氧化物歧化酶抗顺铂诱导的肾损伤效应

Anti-cisplatin-induced Renal-injury Effect of Human Manganese Superoxide Dismutase with Leader Peptide

目的 探讨前导肽的融合对人锰超氧化物歧化酶(SOD2)结构以及抗顺铂(DDP)诱导的肾损伤效应。方法 通过结构预测和SOD比活力测定分析线粒体靶向序列(MTS)对SOD2构效的影响;建立昆明(KM)小鼠DDP损伤模型,以阿米福汀(AMFT)为阳性对照,测定小鼠肾功能、肾脏指数、肾脏抗氧化能力,同时观察肾脏表观及病理变化,以评估MTS-SOD2抗DDP诱导的肾损伤效应。结果 MTS前导肽对SOD2的二三级结构有一定影响,但也使MTS-SOD2蛋白的比活力提高。预给予中剂量MTS-SOD2(0.84 mg/kg)可以使损伤鼠肾脏丙二醛(MDA)水平显著降低,SOD活力和总抗氧化能力(T-AOC)显著增加,进而减少肾脏病理损伤,维持肾功能,整体效果与200 mg/kg AMFT相当甚至优于后者。结论 MTS前导肽既增强了SOD2的活性,又使其因具有跨膜功能而发挥优异的抗DDP诱导的肾损伤效应。

Objective To investigate the effect of the fusion of leader peptide on the structure of human manganese superoxide dismutase(SOD2)and anti-cisplatin(DDP)-induced renal injury.Methods The effect of mitochondrion targeting sequence(MTS)on the structure and activity of SOD2 was analyzed by structure prediction and superoxide dismutase(SOD)specific-activity determination.The DDP injury model of Kunming(KM)mice was established,and amifostine(AMFT)was set as a positive control.Indicators such as kidney index,renal function,kidney antioxidant capacity,and appearance and pathology changes of mice kidney were used to evaluate the effect of MTS-SOD2 against DDP-induced kidney injury.Results The MTS leader peptide seemed to change the secondary and tertiary structures of SOD2 to some extent,but it also increased the specific activity of the MTS-SOD2 protein.Pre-administration of a medium dose of MTS-SOD2(0.84 mg/kg)before the use of DDP significantly reduced the level of renal malondialdehyde and increased the SOD activity and total antioxidant capacity(T-AOC)in the kidney,thereby reducing the renal pathological damage and consequently maintaining renal function.The overall protective effect of MTS-SOD2 was comparable to or even better than that of 200 mg/kg AMFT.Conclusion The MTS leader peptide enhances the activity of SOD2 and confers it with an excellent anti-DDP-induced renal-injury effect because of its transmembrane function.