Endocrine Abstracts

Hyponatremia is the most frequent electrolytic disorder in clinical practice. It is estimated that in about 50% of cases hyponatremia is secondary to the syndrome of inappropriate antidiuresis (SIAD). Hyponatremia is associated with a worse outcome and with increased mortality in several diseases, including cancer. In vitro and in vivo evidence shows that low [Na⁺ ] is associated with neurological and extra-neurological alterations, which include for instance bone demineralization, leading to osteoporosis. In order to better elucidate tissue alterations associated with reduced [Na⁺ ], we developed and characterized an in vivo model of hyponatremia secondary to SIAD, induced in a total of 38 Fox ^nu/nu mice by subcutaneous infusion of the vasopressin analogue 1-deamino [8-D-arginine] vasopressin (dDAVP) via osmotic minipumps for a total of 14 days. Mice were randomly divided into three experimental groups and sacrificed at different times: two groups were infused with 0.3 and 0.5 ng/h dDAVP, respectively (A and B, n=11 for each group) and one control group was infused with isotonic saline solution (0.9% NaCl) (C, n=16). After the initiation of dDAVP infusion, mice gained weight, urinary volume was reduced and urine osmolarity increased. Starting from a baseline serum [Na⁺ ] of 151 ± 1.57 mEq/l (mean+SE), a serum [Na⁺ ] of 131.01 ± 5.76 mEq/l and 116.7 mEq/l ± 5.19 mEq/l was achieved in group A and B, respectively, at the end of dDAVP administration. The day of sacrifice different organs were collected, fixed and processed for histological analysis. In particular, we focused on liver, because evident morphological alterations were observed in hyponatremic mice. Specifically, peripheric steatosis was observed, with accumulation of lipid droplets into hepatocytes and collagen fibers. Western blot analysis of proteins involved in hepatic lipid metabolism confirmed the increased lipogenic status associated with the progressive reduction of serum [Na⁺ ]. The expression of the heme oxigenase-1 (HMOX1) gene, which we had previously found to be upregulated in low [Na⁺ ], significantly increased both in hepatic stellate cells and in Kupffer cells, as confirmed by serial immunohistochemical analysis for α-Smooth Muscle Actin, F480 and HMOX-1. In view of these original findings, we hypothesize that hyponatremia might be consider a trigger for liver steatosis. This observation has a potential impact on clinical grounds, also because liver steatosis is known to possibly evolve into cirrhosis and ultimately into cancer.