title: A selective EP4 PGE2 receptor agonist  alleviates disease in a new mouse model  of X-linked nephrogenic diabetes insipidus.
abstract: X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present,no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen.Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology.These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI.
authors.affiliation: Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases,NIH, Bethesda, Maryland, USA.
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Chung-Lin
authors.initials: CL
authors.lastname: Chou
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Stasia A
authors.initials: SA
authors.lastname: Anderson
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Mark A
authors.initials: MA
authors.lastname: Knepper
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D051400:Aquaporin 3 / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007671:Kidney Concentrating Ability; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism
chemical_list: C496024:Aqp2 protein, mouse; C496028:Aqp3 protein, mouse; D051399:Aquaporin 2; D008738:Methyl Ethers; C461399:ONO-AE1-329; C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017483:Receptors, Vasopressin; D051400:Aquaporin 3