Abstract
SIRT6 is a protein deacetylase, involved in various intracellular processes including suppression of glycolysis and DNA repair. Aldose Reductase (AR), first enzyme of polyol pathway, was proposed to be indirectly associated to these SIRT6 linked processes. Despite these associations, presence of SIRT6 based regulation of AR still remains ambiguous. Thus, regulation of AR expression by SIRT6 was investigated under hyperosmotic stress. A unique model of osmotic stress in U937 cells was used to demonstrate the presence of a potential link between SIRT6 and AR expression. By overexpressing SIRT6 in HeLa cells under hyperosmotic stress, its role on upregulation of AR was revealed. In parallel, increased SIRT6 activity was shown to upregulate AR in U937 cells under hyperosmotic milieu by using pharmacological modulators. Since these modulators also target SIRT1, binding of the inhibitor, Ex-527, specifically to SIRT6 was analyzed in silico. Computational observations indicated that Ex-527 may also target SIRT6 active site residues under high salt concentration, thus, validating in vitro findings. Based on these evidences, a novel regulatory step by SIRT6, modifying AR expression under hyperosmotic stress was presented and its possible interactions with intracellular machinery was discussed.
Highlights
A well-established target of the transcription factor NFAT5, aldose reductase (AR) is responsible from reduction of various substrates including glucose, as well as, atherogenesis related aldehydes [1,2,3]
In order to control for excessive cell death that might interfere with the data obtained, 100 mM NaCl treatment was analyzed in terms of cellular viability in U937 and HeLa cells (S1 Fig). 16 hrs of 100 mM NaCl treatment diminished metabolic activity in a statistically insignificant manner, in both cell lines, indicating 100 mM NaCl treatment may be used for further analysis (p > 0.05) (S1 Fig)
At 200 nM Trichostatin A (TSA) pretreatment, an increased nuclear SIRT6 expression was accompanied by increased nuclear NFAT5 and total AR expressions, compared with hyperosmotic stress alone (p < 0.05) (Fig 1A Lanes 6 and 7 and S2A and S2C Fig and Fig 1B Lanes 2 and 3 and S3A Fig)
Summary
A well-established target of the transcription factor NFAT5 (nuclear factor of activated T-cells 5), aldose reductase (AR) is responsible from reduction of various substrates including glucose, as well as, atherogenesis related aldehydes [1,2,3]. Despite its protective role against hyperosmotic stress, this enzyme was shown to be involved in several aspects of diabetic vascular complications including neuropathy, nephropathy, retinopathy and atherosclerosis [4,5,6,7]. SIRT6 and Aldose Reductase Expression alternative approach towards AR would be the fine tuning of its expression level, using other intracellular effectors [8] Among these possible factors regulating AR expression, our group recently identified sirtuin (SIRT1)—poly-(ADP-ribose) polymerase (PARP1) axis regulating NFAT5 dependent AR expression under osmotic stress [9]. Since this axis was shown to be in crosstalk with sirtuin (SIRT6) in other experimental settings, it was proposed that SIRT6 may regulate AR expression [10, 11]
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