Ecelbarger Carolyn A, Murase Takashi, Tian Ying, Nielsen Soren, Knepper Mark A, Verbalis Joseph G
Department of Medicine, Division of Endocrinology and Metabolism, Building D, Room 232, 4000 Reservoir Road NW, Georgetown University, Washington, DC 20007, USA.
Prog Brain Res. 2002;139:75-84. doi: 10.1016/s0079-6123(02)39008-3.
Hyponatremia, defined as a serum sodium < 135 mmol/l, is one of the most commonly encountered and serious electrolyte disorders of clinical medicine. The predominant cause of hyponatremia is an inappropriate elevation of circulating vasopressin levels relative to serum osmolality or the 'syndrome of inappropriate antidiuretic hormone secretion' (SIADH). Fortunately, the degree of the hyponatremia is limited by a process that counters the water-retaining action of vasopressin, namely 'vasopressin escape'. Vasopressin escape is characterized by a sudden increase in urine volume with a decrease in urine osmolality independent of circulating vasopressin levels. Until recently, little was known about the molecular mechanisms underlying escape. In the 1980s, we developed an animal model for vasopressin escape in which male Sprague-Dawley rats were infused with dDAVP, a V2-receptor-selective agonist of vasopressin, while being fed a liquid diet. Rats drank a lot of water in order to get the calories they desired. Using this model, we demonstrated that the onset of vasopressin escape (increased urine volume coupled to decreased urine osmolality) coincided temporally with a marked decrease in renal aquaporin-2 (water channel) protein and mRNA expression in renal collecting ducts. This protein reduction was reversible and correlated to decreased water permeability of the collecting duct. Studies examining the mechanisms underlying AQP2 decrease revealed a decrease in V2-receptor mRNA expression and binding, as well as a decrease in cyclic AMP production in response to acute-dDAVP challenge in collecting duct suspensions from these escape animals. Additional studies showed an increase in sodium transporters of the distal tubule. These changes, hypothetically, might help to attenuate the hyponatremia. Future studies are needed to fully elucidate systemic, intra-organ, and cellular signaling responsible for the physiological phenomenon of vasopressin escape.
低钠血症定义为血清钠<135 mmol/L，是临床医学中最常见且严重的电解质紊乱之一。低钠血症的主要原因是循环中血管加压素水平相对于血清渗透压不适当升高，即“抗利尿激素分泌不当综合征”（SIADH）。幸运的是，低钠血症的程度受到一种对抗血管加压素保水作用的过程的限制，即“血管加压素逃逸”。血管加压素逃逸的特征是尿量突然增加，尿渗透压降低，且与循环血管加压素水平无关。直到最近，人们对逃逸背后的分子机制知之甚少。在20世纪80年代，我们开发了一种血管加压素逃逸的动物模型，给雄性Sprague-Dawley大鼠输注dDAVP（血管加压素的V2受体选择性激动剂），同时给予液体饮食。大鼠为了获取所需热量而大量饮水。利用这个模型，我们证明血管加压素逃逸的开始（尿量增加伴尿渗透压降低）在时间上与肾集合管中肾水通道蛋白-2（水通道）的蛋白质和mRNA表达显著降低相吻合。这种蛋白质减少是可逆的，并且与集合管水通透性降低相关。研究AQP2减少的机制发现，V2受体mRNA表达和结合减少，以及在这些逃逸动物的集合管悬浮液中，对急性dDAVP刺激的环磷酸腺苷产生减少。进一步的研究表明远端小管钠转运体增加。假设这些变化可能有助于减轻低钠血症。需要进一步的研究来全面阐明负责血管加压素逃逸这一生理现象的全身、器官内和细胞信号传导。
