Abnormal osmotic regulation in trpv4-/- mice
Abnormal osmotic regulation in trpv4-/- mice
复制标题
DOI：
10.1073/pnas.1735416100
复制
发表时间：
2003-11-11
影响因子：
11.1
通讯作者：
Friedman, JM
中科院分区：
文献类型：
--
作者：
Liedtke, W;Friedman, JM
渗透稳态是脊椎动物中最受保护的生理参数之一。然而，人们对渗透调节的分子机制知之甚少。瞬时受体电位通道香草酸亚家族（TRPV4）是一种渗透激活的离子通道，在哺乳动物中枢神经系统的室周器官中表达，是渗透感应的重要部位。我们培育了trpv4缺失小鼠并观察到它们的渗透调节异常。与野生型同窝小鼠相比，trpv4(-/-) 小鼠喝的水更少，并且渗透压更高，这一发现在施用和不施用高渗盐水的情况下均可见。此外，在高渗攻击后，trpv4(-/-)小鼠的血浆抗利尿激素水平显着低于野生型同窝小鼠。连续SC输注抗利尿激素类似物 dDAVP 会导致 trpv4(-/-) 小鼠全身性低渗，尽管它们的肾水重吸收能力是正常的。因此，trpv4(-/-) 小鼠对高渗和低渗刺激的反应均受损。高渗性攻击后，与野生型小鼠相比，trpv4(-/-) 小鼠的心室周围器官（终板血管器官）中 c-FOS 的表达显着降低。这一发现表明 trpv4(-/-) 小鼠的中枢神经系统渗透感应功能受损。这些数据表明 TRPV4 对于渗透压变化的正常响应是必需的，并且在 CMS 中充当渗透传感器。
Osmotic homeostasis is one of the most aggressively defended physiological parameters in vertebrates. However, the molecular mechanisms underlying osmotic regulation are poorly understood. The transient receptor potential channel, vanilloid subfamily (TRPV4), is an osmotically activated ion channel that is expressed in circumventricular organs in the mammalian CNS, which is an important site of osmotic sensing. We have generated trpv4-null mice and observed abnormalities of their osmotic regulation. trpv4(-/-) mice drank less water and became more hyperosmolar than did wild-type littermates, a finding that was seen with and without administration of hypertonic saline. In addition, plasma levels of antidiuretic hormone were significantly lower in trpv4(-/-) mice than in wild-type littermates after a hyperosmotic challenge. Continuous s.c. infusion of the antidiuretic hormone analogue, dDAVP, resulted in systemic hypotonicity in trpv4(-/-) mice, despite the fact that their renal water reabsorption capacity was normal. Thus, the response to both hyper- and hypoosmolar stimuli is impaired in trpv4(-/-) mice. After a hyperosmolar challenge, there was markedly reduced expression of c-FOS in the circumventricular organ, the organum vasculosum of the lamina terminalis, of trpv4(-/-) mice compared with wild-type mice. This finding suggests that there is an impairment of osmotic sensing in the CNS of trpv4(-/-) mice. These data indicate that TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CMS.