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Cell Physiol Biochem. 2011;27(6):681-90. doi: 10.1159/000330077. Epub 2011 Jun 17.

NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway.

Author information

1
Department of Nephrology, Kidney Center and Key Lab of the People's Liberation Army, General Hospital of People's Liberation Army, Beijing, People's Republic of China.

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.

PMID:
21691086
DOI:
10.1159/000330077
[Indexed for MEDLINE]
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