SIRT1 contributes to aldose reductase expression through modulating NFAT5 under osmotic stress: In vitro and in silico insights

Timuçin, Ahmet Can; Bodur, Çağrı; Başağa, Hüveyda

doi:10.1016/j.cellsig.2015.08.013

Cited by 8 publications

(17 citation statements)

References 92 publications

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“…NFAT5 is highly expressed in OA chondrocytes [ 18 ] and is positively regulated by Sirt1 [ 16 ]. ChIP assay was performed to assess the role of Sirt1 in the regulation of NFAT5 in IL-1β-insulted chondrocytes.…”

Section: Resultsmentioning

confidence: 99%

“…NFAT5 is highly expressed in OA tissues and contributes greatly to the pathogenesis of OA [ 18 ]. NFAT5 is positively regulated by Sirt1 [ 16 ]. In this study, NFAT5 was considerably upregulated by IL-1β stimulation in chondrocytes, but this increase was reduced by melatonin.…”

Section: Discussionmentioning

confidence: 99%

“…Sirt1 transcriptionally activates the expression of nuclear factor of activated T cells 5 (NFAT5) [ 16 ]. NFAT5, known as tonicity-responsive enhancer binding protein, is originally identified as a tonicity-regulated transcription factor involved in the protection of cells from hypertonic stress [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis

Guo

Wen

et al. 2017

Oncotarget

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Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage degradation. Interleukin-1β (IL-1β) contributes to OA pathogenesis by enhancing oxidative stress and inflammation. Melatonin reportedly elicits potent protection against OA. However, the role of melatonin and underlying mechanism in IL-1β-stimulated chondrocytes remain largely unclear. In this study, we found that melatonin inhibited IL-1β-induced toxicity and sirtuin 1 (Sirt1) enhancement in human chondrocytes. Melatonin reduced the IL-1β-increased nicotinamide phosphoribosyltransferase (NAMPT) expression and the NAD+ level in chondrocytes in a Sirt1-dependent manner. In turn, the inhibitory effect of melatonin on Sirt1 was mediated by NAMPT. Moreover, melatonin suppressed IL-1β-induced Sirt1-mediated matrix metalloproteinase (MMP)-3 and MMP-13 production. Melatonin also decreased the Sirt1-steered nuclear factor of activated T cells 5 (NFAT5) expression in IL-1β-challenged chondrocytes. NFAT5 depletion mimicked the suppressive effects of melatonin on IL-1β-elevated production of inflammatory mediators, including tumor necrosis factor-α (TNF-α), IL-1β, prostaglandin E2 (PGE2), and nitric oxide (NO) in chondrocytes. TNF-α, IL-1β, PGE2, or NO decrease caused the similar reduction of MMP-3 and MMP-13 by melatonin in IL-1β-insulted chondrocytes. Highly consistent with in vitro findings, in vivo results demonstrated that melatonin repressed the expression of relevant genes in rat OA pathogenesis in anterior cruciate ligament transection model. Overall, these results indicate that melatonin effectively reduced IL-1β-induced MMP production by inhibiting Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes, suggesting melatonin as a potential therapeutic alternative for chondroprotection of OA patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis

Guo

Wen

et al. 2017

Oncotarget

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“…Cell culture and their treatments were performed as previously described with minor modifications [ 9 ]. U937, human histiocytic lymphoma cell line, cultured in RPMI-1640 with 5 mM glucose, 10% FBS, 2 mM glutamine and 100 IU/ml penicillin/streptomycin, in a humidified incubator with an atmosphere of 5% CO 2 , at 37°C [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, an 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 sirtuin1 (SIRT1)—poly-(ADP-ribose) polymerase1 (PARP1) axis regulating NFAT5 dependent AR expression under osmotic stress [ 9 ]. Since this axis was shown to be in crosstalk with sirtuin6 (SIRT6) in other experimental settings, it was also proposed that SIRT6 may also regulate AR expression [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

SIRT6 Is a Positive Regulator of Aldose Reductase Expression in U937 and HeLa cells under Osmotic Stress: In Vitro and In Silico Insights

Timuçin

Başağa

2016

PLoS ONE

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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.

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NFAT5 protects astrocytes against oxygen–glucose–serum deprivation/restoration damage via the SIRT1/Nrf2 pathway

Xia

et al. 2016

J Mol Neurosci

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Nuclear factor of activated T cells (NFAT) is a multifunctional cytokine family. NFAT5 was recently reported to be involved in many neuronal functions, but its specific function remains unclear. In this study, our aim is to investigate whether NFAT5 overexpression can protect astrocytes against oxygen-glucose-serum deprivation/restoration (OGSD/R) damage. In vivo, rats were subjected to ischemia-reperfusion injury, resulting in increased water content, infarct volume, and expression of NFAT5 protein in rat spinal cord. After primary culture for spinal cord astrocytes, the in vitro OGSD/R model was established. The results of the CCK8 assay and flow cytometry showed that, in the OGSD/R group, astrocyte cell viability was downregulated, but astrocyte apoptosis increased. Caspase 3 activity increased as well. Levels of NFAT5, as detected by real-time quantitative PCR and western blot, decreased under OGSD/R, as did SIRT1. Commercial kits for activity assays were used to show that OGSD/R inhibited SIRT1 activation but accelerated SOD activation after OGSD/R. Next, pcDNA-NFAT5 or NFAT5 siRNA was transfected into astrocytes. Overexpression of NFAT5 not only promoted the survival of the astrocytes and SIRT1 activation under OGSD/R but also inhibited cell apoptosis and SOD activation. Moreover, overexpression of NFAT5 apparently diminished histone acetylation and promoted the nuclear transport of Nrf2. Our results show that NFAT5 protects spinal astrocytes in a manner that depends on activation of the SIRT1/Nrf2 pathway. These findings present a novel potential molecular mechanism for NFAT5 therapy in the context of spinal cord injury.

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SIRT1 contributes to aldose reductase expression through modulating NFAT5 under osmotic stress: In vitro and in silico insights

Cited by 8 publications

References 92 publications

Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis

Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis

SIRT6 Is a Positive Regulator of Aldose Reductase Expression in U937 and HeLa cells under Osmotic Stress: In Vitro and In Silico Insights

NFAT5 protects astrocytes against oxygen–glucose–serum deprivation/restoration damage via the SIRT1/Nrf2 pathway

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