Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions
Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions
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DOI：
10.1073/pnas.0511211103
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发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
King, LS
中科院分区：
文献类型：
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作者：
Sidhaye, VK;Güler, AD;King, LS
Aquaporin-5 (AQP5) 在肺、角膜和各种分泌腺的上皮细胞中表达，这些部位是细胞外渗透压波动的部位。高渗水通道蛋白 (AQP) 诱导已被描述，但关于低渗环境对 AQP 丰度的影响知之甚少。我们报告说，当小鼠肺上皮细胞暴露于低渗介质时，观察到 AQP5 丰度的密切响应性下降。 AQP5 的低渗还原可被钌红、甲烷酰胺和咪康唑阻断，这些药物可抑制肺上皮细胞中存在的阳离子通道瞬时受体电位香草酸 (TRPV) 4。多项观察结果表明，TRPV4 参与 AQP5 的低渗降低，包括需要细胞外钙来实现 AQP5 的降低；低渗刺激后小鼠肺上皮 (MILE) 细胞的细胞内钙增加；添加 TRPV4 激动剂 4a-佛波醇-12,13-二癸酸酯 (4a-PDD) 后 AQP5 丰度降低。同样，在体内向小鼠气管中添加低渗 PBS 会在 1 小时内降低 AQP5，这种作用被钌红阻断。为了确认功能性相互作用，AQP5 在对照或表达 TRPV4 的人胚肾 (HEK) 细胞中表达。仅在 TRPV4 存在时观察到 AQP5 的低渗还原，并被钌红阻断。结合早期的研究，这些观察结果表明 AQP5 丰度在一系列渗透压范围内受到严格调节，并且细胞外低渗性导致的 AQP5 减少可以由 TRPV4 介导。这些发现与肺和其他器官上皮细胞膜水渗透性和水稳态的调节直接相关。
Aquaporin-5 (AQP5) is expressed in epithelia of lung, cornea, and various secretory glands, sites where extracellular osmolality is known to fluctuate. Hypertonic aquaporin (AQP) induction has been described, but little is known about the effects of a hypotonic environment on AQP abundance. We report that, when mouse lung epithelial cells were exposed to hypotonic medium, a close-responsive decrease in AQP5 abundance was observed. Hypotonic reduction of AQP5 was blocked by ruthenium red, methanandamide, and miconazole, agents that inhibit the cation channel transient receptor potential vanilloid (TRPV) 4 present in lung epithelial cells. Several observations indicate that TRPV4 participates in hypotonic reduction of AQP5, including a requirement for extracellular calcium to achieve AQP5 reduction; an increase in intracellular calcium in mouse lung epithelial (MILE) cells after hypotonic stimulation; and reduction of AQP5 abundance after addition of the TRPV4 agonist 4a-Phorbol-12,13-didecanoate (4a-PDD). Similarly, addition of hypotonic PBS to mouse trachea in vivo decreased AQP5 within 1 h, an effect blocked by ruthenium red. To confirm a functional interaction, AQP5 was expressed in control or TRPV4-expressing human embryonic kidney (HEK) cells. Hypotonic reduction of AQP5 was observed only in the presence of TRPV4 and was blocked by ruthenium red. Combined with earlier studies, these observations indicate that AQP5 abundance is tightly regulated along a range of osmolalities and that AQP5 reduction by extracellular hypotonicity can be mediated by TRPV4. These findings have direct relevance to regulation of membrane water permeability and water homeostasis in epithelia of the lung and other organs.