Hyponatremia, i.e., the presence of a serum sodium concentration ([Na+]) < 136 mEq/L, is the most frequent electrolyte imbalance in the elderly and in hospitalized patients. Symptoms of acute hyponatremia, whose main target is the central nervous system, are explained by the “osmotic theory” and the neuronal swelling secondary to decreased extracellular osmolality, which determines cerebral oedema. Following the description of neurological and systemic manifestations even in mild and chronic hyponatremia, in the last decade reduced extracellular [Na+] was associated with detrimental effects on cellular homeostasis independently of hypoosmolality. Most of these alterations appeared to be elicited by oxidative stress. In this review, we focus on the role of oxidative stress on both osmolality-dependent and -independent impairment of cell and tissue functions observed in hyponatremic conditions. Furthermore, basic and clinical research suggested that oxidative stress appears to be a common denominator of the degenerative processes related to aging, cancer progression, and hyponatremia. Of note, low [Na+] is able to exacerbate multiple manifestations of senescence and to decrease progression-free and overall survival in oncologic patients.
Purpose Hyponatremia is the most frequent electrolytic disorder in clinical practice. In addition to neurological symptoms, hyponatremia, even when mild/moderate and chronic, has been related to other manifestations, such as bone demineralization and increased risk of fractures. To better elucidate tissue alterations associated with reduced serum sodium concentration [Na+], we developed an in vivo model of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. Methods and results Hyponatremia was induced in Foxn1nu/nu mice by subcutaneous infusion of the vasopressin analog 1-deamino [8-D-arginine] vasopressin (dDAVP) for 14 days via osmotic mini-pumps. Mice in the control group were infused with isotonic saline solution. Serum [Na+] progressively decreased, with a nadir of 123.4 ± 2.3 mEq/L (mean ± SD, dDAVP 0.3 ng/h) and 111.6 ± 4.7 mEq/L (mean ± SD, dDAVP 0.5 ng/h). Evident signs of liver steatofibrosis were observed at histology in hyponatremic mice. Accordingly, the expression of proteins involved in lipid metabolism (SREBP-1, PPARα and PPARγ) and in myofibroblast formation (αSMA and CTGF) significantly increased. Furthermore, heme oxygenase 1 expression was up-regulated in Kupffer and hepatic stellate cells in the liver of hyponatremic mice. Testis alterations were also observed. In particular, the thickness of the seminiferous epithelium appeared reduced. The expression levels of PCNA and PTMA, which are involved in DNA replication and germ cells maturation, were markedly reduced in the testis of hyponatremic mice. Conclusion Overall, these findings shed new light on the possible consequences of chronic hyponatremia and prompt a more thorough evaluation of hyponatremic patients.
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