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首页> 外文期刊>Cell cycle >Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage
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Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage

机译:减少糖尿病肾细胞损伤的新型保护机制:AICAR激活AMPK可增加NRF2 / OGG1蛋白并减少氧化性DNA损伤

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Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser792 and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy.
机译:最近,有人提出在糖尿病期间将肾细胞暴露于高葡萄糖(HG)中可能与肾损伤有关。在本研究中,我们调查了AICAR处理调节暴露于HG的肾近端肾小管小鼠细胞和db / db小鼠肾脏中的DNA修复酶,8-oxoG-DNA糖基化酶(OGG1)的潜在机制。 HG处理2天的细胞显示OGG1启动子活性以及OGG1和Nrf2蛋白表达受到抑制。另外,AICAR激活AMPK导致Ser792的猛禽磷酸化增加,并通过上调Nrf2导致OGG1的启动子活性增加。 DN-AMPK和猛禽对AMPK的下调以及siRNA对Nrf2的下调导致启动子活性和OGG1蛋白表达显着下降。另一方面,DN-Akt对Akt的下调和siRNA对rictor的下调导致Nrf2和OGG1的启动子活性和蛋白表达显着增加。此外,凝胶位移分析显示在用HG处理的细胞中Nrf2与OGG1启动子的结合减少,而用AICAR处理的细胞逆转了HG的作用。此外,与未治疗的小鼠相比,经AICAR治疗的db / db小鼠的AMPK和猛禽磷酸化以及OGG1和Nrf2蛋白表达显着增加,与氧化性DNA损伤(8-oxodG)显着降低有关。总之,我们的数据提供了一种新型的保护机制,AICAR可以通过这种机制防止糖尿病中的肾细胞损害以及高血糖症的并发症,特别是针对肾病。

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