Department of Endocrinology and Metabolism, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Endocr J. 2021 Jan 28;68(1):31-43. doi: 10.1507/endocrj.EJ20-0289. Epub 2020 Sep 2.
Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia. Appropriate animal models are crucial for investigating the pathophysiology of SIADH. A rat model of SIADH has been generally used and mouse models have been rarely used. In this study, we developed a mouse model of chronic SIADH in which stable and sustained hyponatremia occurred after 3-week continuous infusion of the vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) and liquid diet feeding to produce chronic water loading. Weight gain in chronic SIADH mice at week 2 and 3 after starting dDAVP injection was similar to that of control mice, suggesting that the animals adapted to chronic hyponatremia and grew up normally. AQP2 expression in the kidney, which reflects the renal action of vasopressin, was decreased in dDAVP-infused water-loaded mice as compared with control mice that received the same dDAVP infusion but were fed pelleted chow. These results suggest that "vasopressin escape" occurred, which is an important process for limiting potentially fatal severe hyponatremia. Behavioral analyses using the contextual and cued fear conditioning test and T-maze test demonstrated cognitive impairment, especially working memory impairment, in chronic SIADH mice, which was partially restored after correcting hyponatremia. Our results suggest that vasopressin escape occurred in chronic SIADH mice and that chronic hyponatremia contributed to their memory impairment.
最近，即使是轻度的慢性低钠血症也已显示与生活质量差和死亡率高有关。但是，低钠血症导致这些症状的机制仍有待阐明。抗利尿激素分泌不当综合征（SIADH）是低钠血症的主要原因。适当的动物模型对于研究 SIADH 的病理生理学至关重要。通常使用大鼠模型来研究 SIADH，而很少使用小鼠模型。在这项研究中，我们开发了一种慢性 SIADH 的小鼠模型，该模型在连续 3 周输注血管加压素 V2 受体激动剂 1-脱氨基-8-D-精氨酸血管加压素（dDAVP）和液体饮食喂养以产生慢性水负荷后会发生稳定且持续的低钠血症。在开始 dDAVP 注射后的第 2 周和第 3 周，慢性 SIADH 小鼠的体重增加与对照小鼠相似，这表明动物适应了慢性低钠血症并正常生长。与接受相同 dDAVP 输注但喂食颗粒状食物的对照小鼠相比，肾脏中的 AQP2 表达（反映了血管加压素的肾脏作用）在接受 dDAVP 输注和水负荷的小鼠中降低。这些结果表明发生了“血管加压素逃逸”，这是限制潜在致命性严重低钠血症的重要过程。使用情境和线索恐惧条件反射测试和 T 迷宫测试进行的行为分析表明，慢性 SIADH 小鼠存在认知障碍，尤其是工作记忆障碍，在纠正低钠血症后部分恢复。我们的结果表明，血管加压素逃逸发生在慢性 SIADH 小鼠中，慢性低钠血症导致了它们的记忆障碍。
