TITLE

NAD Blocks High Glucose Induced Mesangial Hypertrophy via Activation of the Sirtuins-AMPK-mTOR Pathway

AUTHOR(S)
Zhuo, Li; Fu, Bo; Bai, Xueyuan; Zhang, Bin; Wu, Lingling; Cui, Jing; Cui, Shaoyuan; Wei, Ribao; Chen, Xiangmei; Cai, Guangyan
PUB. DATE
June 2011
SOURCE
Cellular Physiology & Biochemistry (Karger AG);2011, Vol. 27 Issue 6, p681
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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. Copyright © 2011 S. Karger AG, Basel
ACCESSION #
61407431

 

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