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

Cellular Physiology and Biochemistry

关键词: NAD;    Sirtuins;    AMPK;    mTOR;    Mesangial hypertrophy;   

DOI  :  10.1159/000330077

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 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.

【 授权许可】

CC BY-NC-ND