Abstract
Background
Hyponatremia is associated with negative clinical outcomes even when chronic and mild. It is also known that hyponatremia treatment should be appropriately performed, to avoid dramatic consequences possibly leading to death. We have previously demonstrated that chronically low extracellular [Na+], independently of reduced osmolality, is associated with signs of neuronal cell distress, possibly involving oxidative stress.
Aim
The aim of the present study was to assess whether the return to normal extracellular [Na+] is able to revert neuronal cell damage.
Methods
After exposing SH-SY5Y and SK-N-AS cells to low [Na+] and returning to normal [Na+], we analyzed cell viability by MTS assay, ROS accumulation by FASCan and expression of anti-apoptotic genes.
Results
We found that the viability of cells was restored upon return to normal [Na+]. However, when more subtle signs of cell distress were assessed, such as the expression level of the anti-apoptotic genes Bcl-2 and DHCR24 or of the heme oxygenase 1 gene, a complete return to basal values was not observed, in particular in SK-N-AS, even when [Na+] was gradually increased. We also demonstrated that the amount of ROS significantly increased in low [Na+], thus confirming that oxidative stress appears to contribute to the effects of low [Na+] on cell homeostasis.
Conclusions
Overall, this study provided the first demonstration that the correction of chronically low extracellular [Na+] may not be able to revert all the cell alterations associated with reduced [Na+]. These results suggest that prompt hyponatremia treatment might prevent possible residual abnormalities.
Similar content being viewed by others
References
Adrogué HJ, Madias NE (2000) Hyponatremia. New Eng J Med 342:1493–1499
Thompson C, Hoorn EJ (2012) Hyponatraemia: an overview of frequency, clinical presentation and complications. Best Prac Res Clin En 26:S1–S6
Wald R, Jaber BL, Price LL (2010) Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 170:294–302
King JD, Rosner MH (2010) Osmotic demyelination syndrome. Am J Med Sci 339:561–567
Corona G, Simonetti L, Giuliani C et al (2014) A case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum. BMC Endocr Disord 11:14–34
Renneboog B, Musch W, Vandemergel X et al (2006) Mild chronic hyponatremia is associated with falls, unsteadiness and attention deficits. Am J Med 119:71–78
Kinsella S, Moran S, Sullivan MO et al (2010) Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol 5:275–280
Hoorn EJ, Liamis G, Zietse R, Zillikens MC (2011) Hyponatremia and bone: an emerging relationship. Nat Rev Endocrinol 25:33–39
Verbalis JG, Barsony J, Sugimura Y et al (2010) Hyponatremia-induced osteoporosis. JBMR 25:554–563
Barsony J, Manigrasso MB, Xu Q et al (2013) Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats. Age (Dordr) 35:271–288
Corona G, Giuliani C, Parenti G et al (2013) Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS one 18:e80451
Barsony J, Sugimura Y, Verbalis JG (2011) Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. JBC 286:10864–10875
Benvenuti S, Deledda C, Luciani P et al (2013) Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia. NeuroMol Med 15:493–503
Zinkel S, Gross A, Yang E (2006) BCL2 family in DNA damage and cell cycle control. Cell Death Differ 13:1351–1359
Sasi N, Hwang M, Jaboin J et al (2009) Regulated cell death pathways: new twists in modulation of BCL2 family function. Mol Cancer Ther 8:1421–1429
Kontos CK, Christodoulou MI, Scorilas A (2014) Apoptosis-related BCL2-family members: key players in chemotherapy. Anticancer Agents Med Chem 14:353–374
Waterham HR, Koster J, Romeijn GJ et al (2001) Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet 69:685–694
Greeve I, Hermans-Borgmeyer I, Brellinger C et al (2000) The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer’s disease-associated neurodegeneration and oxidative stress. J Neurosci 20:7345–7352
Benvenuti S, Luciani P, Vannelli GB et al (2005) Estrogen and selective estrogen receptor modulators exert neuroprotective effects and stimulate the expression of selective Alzheimer’s disease indicator-1, a recently discovered antiapoptotic gene, in human neuroblast long-term cell cultures. JCEM 90:1775–1782
Bonaccorsi L, Luciani P, Nesi G et al (2008) Androgen receptor regulation of the seladin-1/DHCR24 gene: altered expression in prostate cancer. Lab Invest 88:1049–1056
Benvenuti S, Luciani P, Cellai I et al (2008) Thyroid hormones promote cell differentiation and up-regulate the expression of the seladin-1 gene in in vitro models of human neuronal precursors. JOE 197:437–446
King JD, Rosner MH (2010) Osmotic demyelination syndrome. Am J Med Sci 339:561–567
Ciccarone V, Spengler BA, Meyers MB et al (1989) Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. Cancer Res 49:219–225
Piacentini M, Piredda L, Storace DT et al (1996) Differential growth of N- and S-type human neuroblastoma cells xenografted into SCID mice: correlation with apoptosis. J Pathol 180:415–422
Cellai I, Benvenuti S, Luciani P et al (2006) Antineoplastic effects of rosiglitazone and PPARgamma transactivation in neuroblastoma cells. Brit J Cancer 95:879–888
Chen J (2014) Heme oxygenase in neuroprotection: from mechanisms to therapeutic implications. Rev Neuroscience 25:269–280
Grochot-Przeczek A, Dulak J, Jozkowicz A (2012) Haemoxygenase-1: non-canonical roles in physiology and pathology. Clin Sci 122:93–103
Giuliani C, Cangioli M, Beck-Peccoz P et al (2013) Awareness and management of hyponatraemia: the Italian Hyponatraemia Survey. J Endocrinol Invest 36:693–698
Acknowledgments
This study was supported by Ente Cassa di Risparmio di Firenze and by Otsuka Pharmaceutical. The funding sources had no involvement in the study design, in the collection analysis and interpretation of data and in writing the report.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
We declare that no humans or animals were used by the authors and his collaborators to generate the data reported in this paper.
Informed consent
No informed consent was necessary for the data reported in this paper.
Rights and permissions
About this article
Cite this article
Benvenuti, S., Deledda, C., Luciani, P. et al. Neuronal distress induced by low extracellular sodium in vitro is partially reverted by the return to normal sodium. J Endocrinol Invest 39, 177–184 (2016). https://doi.org/10.1007/s40618-015-0352-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-015-0352-1