title: Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia.
abstract: There is evidence that chronic hyponatremia, even when mild, may cause neurological signs and symptoms. These have been traditionally associated with water movement into nervous cells, as a result of the hypotonic state. The aim of the present study was to determine whether low extracellular sodium directly exerts negative effects on human neuronal cells, independently of reduced osmolality. We exposed neuroblastoma SK-N-AS and SH-SY5Y cells to sustained low extracellular sodium, thus mimicking a condition of chronic hyponatremia, both in the presence of reduced and in the presence of unaltered osmolality. We found that very low sodium (i.e., 115 mmol/L in SK-N-AS and 90 mmol/L in SH-SY5Y) significantly reduced cell viability. However, intermediate low sodium was able to cause cell distress, as assessed by the altered expression of anti-apoptotic genes and the reduced ability to differentiate into a mature neuronal phenotype. Noteworthy, these effects were observed also in the presence of unaltered osmolality. Moreover, we performed a comprehensive microarray analysis in cells maintained in normal sodium or in low sodium and unaltered osmolality, and we found that the most altered pathway included genes involved in "cell death and survival." Among the more than 40 differentially expressed genes, the Heme oxygenase gene, which represents a transcriptional response to oxidative stress, showed the highest increase in the expression level. This study demonstrates that low extracellular sodium causes detrimental effects in neuronal cells that are at least in part independent of reduced osmolality. These findings further support the recommendation to effectively correct hyponatremia, even when mild and chronic.
authors.affiliation: Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Benvenuti
authors.forename: Cristiana
authors.initials: C
authors.lastname: Deledda
authors.forename: Paola
authors.initials: P
authors.lastname: Luciani
authors.forename: Giulia
authors.initials: G
authors.lastname: Modi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bossio
authors.forename: Corinna
authors.initials: C
authors.lastname: Giuliani
authors.forename: Benedetta
authors.initials: B
authors.lastname: Fibbi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Peri
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D002908:Chronic Disease; D045604:Extracellular Fluid / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007010:Hyponatremia / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology; D055495:Neurogenesis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D060888:Real-Time Polymerase Chain Reaction; D012964:Sodium / Q000494:pharmacology*
chemical_list: D012964:Sodium; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1