ArticleProceedings of the National Academy of Sciences of the United States of America2015
Disruption of prostaglandin E2 receptor EP4 impairs urinary concentration via decreasing aquaporin 2 in renal collecting ducts.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 64 citations in OpenAlex.
- Fluid-electrolyte homeostasis requires histone deacetylase function.JCI insight · 2020Pooled it
- Novel Roles of GPCRs in the Renal Collecting Duct.Physiology (Bethesda, Md.) · 2026Review
- The update of prostaglandin E2 receptor subtype 4 (EP4) in inflammatory diseases.Genes & diseases · 2026Review
- Dual Roles of Prostaglandin E2 (PGE2) in Bone Remodeling and Pain Management: Bridging the Gap in Osteoarthritis Research.Mediators of inflammation · 2025Review
- The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population.The Journal of clinical endocrinology and metabolism · 2024Article
- Activation of TGR5 Increases Urine Concentration by Inducing AQP2 and AQP3 Expression in Renal Medullary Collecting Ducts.Kidney diseases (Basel, Switzerland) · 2024Article
- Role of EP4 factor in paediatric type 1 diabetes mellitus: a comprehensive review focusing on the honeymoon period.Pediatric endocrinology, diabetes, and metabolism · 2024Review
- Single hormone or synthetic agonist induces GProceedings of the National Academy of Sciences of the United States of America · 2023Article
- The Link between Prostanoids and Cardiovascular Diseases.International journal of molecular sciences · 2023Review
- Bile acid receptors and renal regulation of water homeostasis.Frontiers in physiology · 2023Review
- Aquaporins in Urinary System.Advances in experimental medicine and biology · 2023Article
- Cell-Specific Actions of the Prostaglandin E-Prostanoid Receptor 4 Attenuating Hypertension: A Dominant Role for Kidney Epithelial Cells Compared With Macrophages.Journal of the American Heart Association · 2022Article
- PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis.Bone research · 2022Article
- Roles of EP Receptors in the Regulation of Fluid Balance and Blood Pressure.Frontiers in endocrinology · 2022Review
- Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats.Frontiers in cardiovascular medicine · 2022Article
- Abnormal expression and the significant prognostic value of aquaporins in clear cell renal cell carcinoma.PloS one · 2022Article
- Myeloid cyclooxygenase-2/prostaglandin E2/E-type prostanoid receptor 4 promotes transcription factor MafB-dependent inflammatory resolution in acute kidney injury.Kidney international · 2022Article
- Updates and Perspectives on Aquaporin-2 and Water Balance Disorders.International journal of molecular sciences · 2021Review
- Comparative quantitation of aquaporin-2 and arginine vasopressin receptor-2 localizations among chronic kidney disease and healthy kidney in dogs.Veterinary world · 2021Article
- Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus.Scientific reports · 2021Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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