| Author |
Huang, Shizheng Han, Qifei Miao, Yifei Kang, Jihong Guan, Youfei Zheng, Senfeng Du, Shengnan Jia, Xiao Cao, Rong Gustafsson, Jan-åke Gao, Min Liu, Jia Zhang, Xiaoyan |
| Description |
Author Affiliation: Gao M ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Cao R ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Du S ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Jia X ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Zheng S ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Huang S ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Han Q ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Liu J ( Department of Physiology, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, 518060, China); Zhang X ( Department of Physiology, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, 518060, China); Miao Y ( Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204); Kang J ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); Gustafsson JÅ ( Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204); Guan Y ( Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China); |
| Abstract |
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. |
| Subject Keyword |
Aquaporin 2 Genetics Kidney Concentrating Ability Kidney Tubules, Collecting Metabolism Receptors, Prostaglandin E, EP4 Subtype Animals Blotting, Western Cell Line Cell Membrane Drug Effects Cells, Cultured Cyclic AMP Cyclic AMP Response Element-Binding Protein Dinoprostone Analogs & Derivatives Biosynthesis Pharmacology Cytology MAP Kinase Signaling System Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Primary Cell Culture Pyrrolidinones RNA Interference Agonists Reverse Transcriptase Polymerase Chain Reaction Research Support, Non-U.S. Gov't Multidisciplinary |
