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首页> 外文期刊>Cellular Physiology and Biochemistry >NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway
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NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway

机译：NAD通过激活sirtuins-AMPK-mTOR途径来阻断高糖诱导的系膜肥大

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摘要

Background/aims-Since the discovery of NAD-dependent deacetylases, Sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress-response of cells. Here we show that high glucose(HG)-induced mesangial hypertrophy is associated with loss of intracellular levels of NAD. This study was designed to investigate the effect of NAD on HG-induced mesangial hypertrophy. Methods-The rat glomerular mesangial cells (MCs) were incubated in HG medium with or without NAD. Afterwards, NAD~+/NADH ratio and enzyme activity of Sirtuins was determined. In addition, the expression analyses of AMPK-mTOR signaling were evaluated by Western blot analysis. Results-We showed that HG induced the NAD ~+/NADH ratio and the levels of SIRT1 and SIRT3 activity decreased as well as mesangial hypertrophy, but NAD was capable of maintaining intracellular NAD~+/NADH ratio and levels of SIRT1 and SIRT3 activity as well as of blocking the HG-induced mesangial hypertrophy in vitro. Activating Sirtuins by NAD blocked the activation of pro-hypertrophic Akt signaling, and augmented the activity of the antihypertrophic AMPK signaling in MCs, which prevented the subsequent induction of mTOR-mediated protein synthesis. By AMPK knockdown, we showed it upregulated phosphorylation of mTOR. In such, the NAD inhibited HG-induced mesangial hypertrophy whereas NAD lost its inhibitory effect in the presence of AMPK siRNA. Conclusion-These results reveal a novel role of NAD as an inhibitor of mesangial hypertrophic signaling, and suggest that prevention of NAD depletion may be critical in the treatment of mesangial hypertrophy.
机译：背景/目的-自从发现NAD依赖的脱乙酰基酶Sirtuins以来，已经认识到维持细胞内NAD的水平对于管理细胞的应激反应至关重要。在这里，我们显示高葡萄糖（HG）诱导的系膜肥大与细胞内NAD水平的丧失有关。这项研究旨在调查NAD对HG诱导的系膜肥大的影响。方法-大鼠肾小球系膜细胞（MCs）在有或没有NAD的HG培养基中孵育。然后，测定Sirtuins的NAD〜// NADH比和酶活性。另外，通过蛋白质印迹分析评估了AMPK-mTOR信号转导的表达分析。结果-我们发现，HG诱导了NAD〜+ / NADH比值的降低，SIRT1和SIRT3活性的水平降低，系膜肥大，但NAD能够维持细胞内NAD〜+ / NADH的比例以及SIRT1和SIRT3的活性。以及在体外阻断HG诱导的系膜肥大。 NAD激活Sirtuins可以阻断促肥大性Akt信号的激活，并增强MC中抗肥大性AMPK信号的活性，从而阻止了随后诱导mTOR介导的蛋白质合成。通过AMPK敲低，我们表明其上调了mTOR的磷酸化。在这种情况下，NAD抑制了HG诱导的系膜肥大，而在AMPK siRNA的存在下NAD失去了其抑制作用。结论-这些结果揭示了NAD作为肾小球膜肥大信号抑制剂的新作用，并表明预防NAD耗竭可能对肾小球膜肥大的治疗至关重要。

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