Disruption of prostaglandin E2 receptor EP4 impairs urinary concentration via decreasing aquaporin 2 in renal collecting ducts
Disruption of prostaglandin E2 receptor EP4 impairs urinary concentration via decreasing aquaporin 2 in renal collecting ducts
复制标题
前列腺素 E2 受体 EP4 的破坏会通过减少肾集合管中的水通道蛋白 2 来损害尿液浓度。
DOI：
10.1073/pnas.1509565112
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发表时间：
2015-07-07
影响因子：
11.1
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
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作者：
Gao, Min;Cao, Rong;Guan, Youfei
抗利尿激素精氨酸加压素是尿液浓度的全身性效应物质。然而，越来越多的证据表明，其他局部产生的因素也可能在调节肾集合管水重吸收方面发挥重要作用。近年来，前列腺素E2(PGE2)受体EP4已成为治疗肾源性尿崩症的潜在靶点，但其潜在作用机制尚不清楚。利用Cre-loxP重组系统建立了肾小管特异性EP4基因敲除小鼠(KSP-Ep4(-/-))和集合管特异性EP4基因敲除小鼠(AQP2-Ep4(-/-))。KSP-Ep4(-/-)和AQP2-Ep4(-/-)小鼠均出现尿浓缩缺陷。KSP-Ep4(-/-)小鼠肾集合管水通道蛋白2(AQP2)丰度降低，顶膜靶向性明显。体外研究表明，药物激活或腺病毒介导的EP4以cAMP/cAMP反应元件结合蛋白依赖的方式过表达EP4后，小鼠原代内髓集合管(IMCD)细胞中AQP2的mRNA和蛋白水平显著上调。此外，EP4的激活或过表达也增加了稳定转染AQP2基因的小鼠IMCD细胞系(IMCD3)中AQP2的膜积聚，主要是通过cAMP/蛋白激酶A和细胞外信号调节激酶途径。综上所述，在生理条件下，肾脏集合管中的EP4受体在调节尿液浓度方面起着重要作用。EP4能够促进AQP2膜靶向和增加AQP2丰度，使其成为治疗包括获得性和先天性尿崩症在内的临床疾病的潜在治疗靶点。
The antidiuretic hormone arginine vasopressin is a systemic effector in urinary concentration. However, increasing evidence suggests that other locally produced factors may also play an important role in the regulation of water reabsorption in renal collecting ducts. Recently, prostaglandin E2 (PGE2) receptor EP4 has emerged as a potential therapeutic target for the treatment of nephrogenic diabetes insipidus, but the underlying mechanism is unknown. To evaluate the role of EP4 in regulating water homeostasis, mice with renal tubule-specific knockout of EP4 (Ksp-EP4(-/-)) and collecting duct-specific knockout of EP4 (AQP2-EP4(-/-)) were generated using the Cre-loxP recombination system. Urine concentrating defect was observed in both Ksp-EP4(-/-) and AQP2-EP4(-/-) mice. Decreased aquaporin 2 (AQP2) abundance and apical membrane targeting in renal collecting ducts were evident in Ksp-EP4(-/-) mice. In vitro studies demonstrated that AQP2 mRNA and protein levels were significantly up-regulated in mouse primary inner medullary collecting duct (IMCD) cells after pharmacological activation or adenovirus-mediated overexpression of EP4 in a cAMP/cAMP-response element binding protein-dependent manner. In addition, EP4 activation or overexpression also increased AQP2 membrane accumulation in a mouse IMCD cell line (IMCD3) stably transfected with the AQP2 gene, mainly through the cAMP/protein kinase A and extracellular signal-regulated kinase pathways. In summary, the EP4 receptor in renal collecting ducts plays an important role in regulating urinary concentration under physiological conditions. The ability of EP4 to promote AQP2 membrane targeting and increase AQP2 abundance makes it a potential therapeutic target for the treatment of clinical disorders including acquired and congenital diabetes insipidus.