Department of Biomedicine, Water and Salt Research Center, Aarhus University, DK-8000 Aarhus C, Denmark.
Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12949-54. doi: 10.1073/pnas.1104691108. Epub 2011 Jul 18.
In the kidney, the actions of vasopressin on its type-2 receptor (V2R) induce increased water reabsorption alongside polyphosphorylation and membrane targeting of the water channel aquaporin-2 (AQP2). Loss-of-function mutations in the V2R cause X-linked nephrogenic diabetes insipidus. Treatment of this condition would require bypassing the V2R to increase AQP2 membrane targeting, but currently no specific pharmacological therapy is available. The present study examined specific E-prostanoid receptors for this purpose. In vitro, prostaglandin E2 (PGE2) and selective agonists for the E-prostanoid receptors EP2 (butaprost) or EP4 (CAY10580) all increased trafficking and ser-264 phosphorylation of AQP2 in Madin-Darby canine kidney cells. Only PGE2 and butaprost increased cAMP and ser-269 phosphorylation of AQP2. Ex vivo, PGE2, butaprost, or CAY10580 increased AQP2 phosphorylation in isolated cortical tubules, whereas PGE2 and butaprost selectively increased AQP2 membrane accumulation in kidney slices. In vivo, a V2R antagonist caused a severe urinary concentrating defect in rats, which was greatly alleviated by treatment with butaprost. In conclusion, EP2 and EP4 agonists increase AQP2 phosphorylation and trafficking, likely through different signaling pathways. Furthermore, EP2 selective agonists can partially compensate for a nonfunctional V2R, providing a rationale for new treatment strategies for hereditary nephrogenic diabetes insipidus.
在肾脏中，血管加压素对其 2 型受体（V2R）的作用诱导水通道 aquaporin-2（AQP2）的多磷酸化和膜靶向，同时增加水的重吸收。V2R 的功能丧失突变导致 X 连锁性肾性尿崩症。这种情况的治疗需要绕过 V2R 以增加 AQP2 的膜靶向，但目前尚无特定的药理学治疗方法。本研究为此目的检查了特定的 E 前列腺素受体。在体外，前列腺素 E2（PGE2）和 E 前列腺素受体的选择性激动剂 EP2（butaprost）或 EP4（CAY10580）均增加了 Madin-Darby 犬肾细胞中 AQP2 的运输和丝氨酸 264 磷酸化。只有 PGE2 和 butaprost 增加了 AQP2 的 cAMP 和丝氨酸 269 磷酸化。在离体皮质小管中，PGE2、butaprost 或 CAY10580 均可增加 AQP2 的磷酸化，而 PGE2 和 butaprost 则可选择性增加肾切片中 AQP2 的膜积累。在体内，V2R 拮抗剂可导致大鼠严重的尿浓缩缺陷，而用 butaprost 治疗可大大缓解。总之，EP2 和 EP4 激动剂增加 AQP2 的磷酸化和运输，可能通过不同的信号通路。此外，EP2 选择性激动剂可以部分补偿无功能的 V2R，为遗传性肾性尿崩症的新治疗策略提供了依据。
