High NaCl Promotes Cellular Senescence

Dmitrieva, Natalia I.; Burg, Maurice B.

doi:10.4161/cc.6.24.5084

Cited by 49 publications

(41 citation statements)

References 52 publications

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“…PAI-1 agarose beads and assay reagents were obtained from EMD Millipore. Paraffin embedding of mouse tissues and immunohistochemical staining were performed as described (49). To quantify vWF protein expression on the diaminobenzidine-stained sections, we used the yellow-CMYK channel method (50).…”

Section: Methodsmentioning

confidence: 99%

Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis

Dmitrieva

Burg

2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypercoagulability increases risk of thrombi that cause cardiovascular events. Here we identify plasma sodium concentration as a factor that modulates blood coagulability by affecting the production of von Willebrand factor (vWF), a key initiator of the clotting cascade. We find that elevation of salt over a range from the lower end of what is normal in blood to the level of severe hypernatremia reversibly increases vWF mRNA in endothelial cells in culture and the rate of vWF secretion from them. The high NaCl increases expression of tonicity-regulated transcription factor NFAT5 and its binding to promoter of vWF gene, suggesting involvement of hypertonic signaling in vWF up-regulation. To elevate NaCl in vivo, we modeled mild dehydration, subjecting mice to water restriction (WR) by feeding them with gel food containing 30% water. Such WR elevates blood sodium from 145.1 ± 0.5 to 150.2 ± 1.3 mmol/L and activates hypertonic signaling, evidenced from increased expression of NFAT5 in tissues. WR increases vWF mRNA in liver and lung and raises vWF protein in blood. Immunostaining of liver revealed increased production of vWF protein by endothelium and increased number of microthrombi inside capillaries. WR also increases blood level of D-dimer, indicative of ongoing coagulation and thrombolysis. Multivariate regression analysis of clinical data from the Atherosclerosis Risk in Communities Study demonstrated that serum sodium significantly contributes to prediction of plasma vWF and risk of stroke. The results indicate that elevation of extracellular sodium within the physiological range raises vWF sufficiently to increase coagulability and risk of thrombosis.blood clotting | HUVEC | osmotic stress

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Section: Methodsmentioning

confidence: 99%

Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis

Dmitrieva

Burg

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Like other animals, C. elegans can adapt to hypertonic stress, but this adaptation decreases lifespan under standard culture conditions (Dmitrieva and Burg, 2007). Standard nematode growth medium (NGM) contains 51 mM NaCl as the major osmolyte.…”

Section: Introductionmentioning

confidence: 99%

“…If animals adapt to hypertonic stress, spontaneous locomotion resumes and glycerol concentrations plateau within hours. Exposure of C. elegans to moderate osmotic stress (200 to 300 mM NaCl) is sufficient to induce these adaptive changes, although animals have decreased brood sizes and shorter lifespan (Dmitrieva and Burg, 2007). However, a recent report suggests lifespan is extended by hypertonic stress (Chandler-Brown et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins

Anderson

Corkins

et al. 2016

Mechanisms of Ageing and Development

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Moderate stress can increase lifespan by hormesis, a beneficial low-level induction of stress response pathways. 5’-fluorodeoxyuridine (FUdR) is commonly used to sterilize Caenorhabditis elegans in aging experiments. However, FUdR alters lifespan in some genotypes and induces resistance to thermal and proteotoxic stress. We report that hypertonic stress in combination with FUdR treatment or inhibition of the FUdR target thymidylate synthase, TYMS-1, extends C. elegans lifespan by up to 30%. By contrast, in the absence of FUdR, hypertonic stress decreases lifespan. Adaptation to hypertonic stress requires diminished Notch signaling and loss of Notch co-ligands leads to lifespan extension only in combination with FUdR. Either FUdR treatment or TYMS-1 loss induced resistance to acute hypertonic stress, anoxia, and thermal stress. FUdR treatment increased expression of DAF-16 FOXO and the osmolyte biosynthesis enzyme GPDH-1. FUdR-induced hypertonic stress resistance was partially dependent on sirtuins and base excision repair (BER) pathways, while FUdR-induced lifespan extension under hypertonic stress conditions requires DAF-16, BER, and sirtuin function. Combined, these results demonstrate that FUdR, through inhibition of TYMS-1, activates stress response pathways in somatic tissues to confer hormetic resistance to acute and chronic stress. C. elegans lifespan studies using FUdR may need re-interpretation in light of this work.

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“…In the absence of extracellular osmolytes, NRK cells are arrested and cannot divide upon constant hypertonic exposure. Cells are then considered unadapted, displaying a flattened shape and spreading over a large area on the surface, as the hypertrophy phenotype described for HeLa cells (62), which could be attributed to cellular senescence (14). Another potential indicator of unadaptation is the modification of the cell cytoskeleton.…”

Section: Organic Osmolytes and Cell Adaptation To Hypertonic Stress: mentioning

confidence: 99%

Gap junctions favor normal rat kidney epithelial cell adaptation to chronic hypertonicity

Desforges

Savarin

Bounedjah

et al. 2011

American Journal of Physiology-Cell Physiology

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Upon hypertonic stress most often resulting from high salinity, cells need to balance their osmotic pressure by accumulating neutral osmolytes called compatible osmolytes like betaine, myo-inositol, and taurine. However, the massive uptake of compatible osmolytes is a slow process compared with other defense mechanisms related to oxidative or heat stress. This is especially critical for cycling cells as they have to double their volume while keeping a hospitable intracellular environment for the molecular machineries. Here we propose that clustered cells can accelerate the supply of compatible osmolytes to cycling cells via the transit, mediated by gap junctions, of compatible osmolytes from arrested to cycling cells. Both experimental results in epithelial normal rat kidney cells and theoretical estimations show that gap junctions indeed play a key role in cell adaptation to chronic hypertonicity. These results can provide basis for a better understanding of the functions of gap junctions in osmoregulation not only for the kidney but also for many other epithelia. In addition to this, we suggest that cancer cells that do not communicate via gap junctions poorly cope with hypertonic environments thus explaining the rare occurrence of cancer coming from the kidney medulla.

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High NaCl Promotes Cellular Senescence

Cited by 49 publications

References 52 publications

Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis

Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis

C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins

Gap junctions favor normal rat kidney epithelial cell adaptation to chronic hypertonicity

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