SRT2104对小鼠糖尿病肾病发病机制及SIRT1/P53/NRF2通路的影响

Effect of SRT2104 on pathogenesis of diabetic nephropathy and the SIRT1/P53/NRF2 pathway

目的研究SRT2104对糖尿病肾病(DN)小鼠肾功能、肾纤维化、肾炎症及肾氧化应激的影响,并探讨其影响机制。方法将36只雄性BABL/c小鼠随机均分为3组:对照组、DN组和DN+S组,后两组小鼠通过连续5 d腹腔注射50 mg/kg的链脲佐菌素建立DN小鼠模型,之后DN+S组小鼠给予含有SRT2104的饮食喂养24周。最后检测各组小鼠的血糖及肾功能指标,以及肾皮质中肾纤维化、肾炎症及肾氧化应激相关指标和SIRT1/P53/NRF2通路分子的水平。结果DN组和DN+S组的血糖均高于对照组(P<0.05),但DN组和DN+S组组间对比无显著差异。DN组小鼠的尿白蛋白和尿肌酐的比率(UACR)、肾重量/胫骨长度、尿素氮(BUN)、血肌酐(SCr)和血β2-微球蛋白(β2-MG)的数值均显著高于对照组(P<0.05),DN+S组显著低于DN组(P<0.05)。DN组小鼠肾皮质中纤维化指标转化生长因子β1(TGF-β1)和结缔组织生长因子(CTGF)的表达、炎症指标纤溶酶原激活剂抑制剂-1(PAI-1)和VCAM-1的表达和氧化应激指标诱导型一氧化氮合酶(iNOS)、活性氧(ROS)和丙二醛(MDA)的水平均显著高于对照组(P<0.05),DN+S组显著低于DN组(P<0.05)。DN+S小鼠肾皮质中SIRT1和NRF2的表达均显著高于DN组(P<0.05),P53乙酰化程度低于DN组(P<0.05)。结论SRT2104可降低DN小鼠肾纤维化、肾炎症及肾氧化应激,改善肾损伤,其机制与SIRT1/P53/NRF-2通路的激活有关。

Objective To investigate the effects of SRT2104 on renal function,renal fibrosis,renal inflammation and renal oxidative stress in diabetic nephropathy(DN)mice,and intend to explore its mechanism.Methods 36 male BABL/c mice were randomly divided into 3 groups,including control group,DN group and DN+S group.The mice in latter two groups were intraperitoneal injected 50 mg/kg streptozotocin for 5 consecutive days to establish DN mice model.Then mice in the DN+S group were fed with a diet containing SRT2104 for 24 weeks.Finally,levels of indexes of blood glucose and renal function,levels of renal fibrosis,renal inflammation and renal oxidative stress related indicators,and expressions of SIRT1/P53/NRF2 pathway molecules were measured.Results The blood glucose levels in the DN group and the DN+S group were higher than those in the control group(P<0.05),but there was no significant difference between the two groups.The ratio of urinary albumin to urinary creatinine(UACR),kidney weight/tibia length,BUN,SCr andβ2-MG in the DN group were significantly higher than those in the control group(P<0.05),those in DN+S group significantly lower than the DN group(P<0.05).The expressions of renal fibrosis indicators TGF-β1 and CTGF,the expression of inflammatory markers PAI-1 and VCAM-1,and the levels of oxidative stress indicators iNOS,ROS and MDA of the renal cortex in the DN group were significantly higher than those of the control group(P<0.05),those in the DN+S group were significantly lower than the DN group(P<0.05).The expressions of SIRT1 and NRF2 in the renal cortex of DN+S mice were significantly higher than those in the DN group(P<0.05),and the degree of P53 acetylation was lower than that in the DN group(P<0.05).Conclusion SRT2104 can reduce renal fibrosis,renal inflammation and renal oxidative stress in DN mice,and improve renal injury.The mechanism maybe related to the activation of SIRT1/P53/NRF-2 pathway.