Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc.
Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc.
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普罗布考通过抑制氧化还原酶 p66Shc 的表达改善糖尿病肾病的肾损伤
DOI：
10.1016/j.redox.2017.07.002
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发表时间：
2017-10
期刊：
影响因子：
11.4
通讯作者：
Sun L
中科院分区：
文献类型：
--
作者：
Yang S;Zhao L;Han Y;Liu Y;Chen C;Zhan M;Xiong X;Zhu X;Xiao L;Hu C;Liu F;Zhou Z;Kanwar YS;Sun L
普罗布考是一种抗高血压药物和一种有效的抗氧化药物，可以延缓糖尿病肾病（DN）的进展，并逆转糖尿病动物模型中的肾脏氧化应激;然而，这些作用的机制仍不清楚。p66 Shc是高糖环境下肾细胞线粒体ROS产生的新的介导因子。我们以前的研究表明，p66 Shc可以作为DN患者肾氧化损伤的生物标志物，并且p66 Shc上调与体内和体外肾损伤相关。在这里，我们确定普罗布考是否通过抑制p66 Shc表达来改善DN的肾损伤。发现DN患者肾脏中SIRT 1、Ac-H3和p66 Shc的表达发生改变。普罗布考还能降低STZ诱导的糖尿病小鼠的血清肌酐、尿蛋白和LDL-c水平，减轻肾脏氧化损伤和纤维化。此外，普罗布考逆转了p-AMPK、SIRT 1、Ac-H3和p66 Shc的表达。相关分析显示p66 Shc表达与p-AMPK和Sirt 1表达及肾损伤程度相关。在体外用p-AMPK和SIRT 1 siRNA预处理HK-2细胞否定了普罗布考的有益作用。此外，我们注意到普罗布考激活p-AMPK和Sirt 1，并通过促进Sirt 1与p66 Shc启动子的结合和调节HG环境下HK-2细胞中Ac-H3的表达来抑制p66 shc mRNA的转录。我们的研究结果首次表明，普罗布考通过AMPK-SIRT 1-AcH 3途径表观遗传抑制p66 Shc表达来改善DN的肾损伤。
Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression. We found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac-H3 expression in HK-2 cells under HG ambience. Our results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway.
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影响因子：
7.3
作者：
Lin, Jamie S.;Shi, Yuanyuan;Peng, Hui;Shen, Xiaojie;Thomas, Sandhya;Wang, Yanlin;Truong, Luan D.;Dryer, Stuart E.;Hu, Zhaoyong;Xu, Jing
通讯作者：
Xu, Jing
影响因子：
13.6
作者：
Kondo, Shuji;Shimizu, Maki;Kagami, Shoji
通讯作者：
Kagami, Shoji
影响因子：
64.5
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
5.1
作者：
Endo, K;Miyashita, Y;Shirai, K
通讯作者：
Shirai, K
线粒体乙醛脱氢酶 (ALDH2) 在 I 型糖尿病引起的心功能障碍中的新型保护机制：AMPK 调节的自噬的作用
DOI：
10.1016/j.bbadis.2014.05.017
发表时间：
2015-02-01
影响因子：
6.2
作者：
Guo, Yuli;Yu, Wenjun;Wang, Haichang
通讯作者：
Wang, Haichang