title: Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation.
abstract: Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify the molecular mechanism(s) of this disease in vivo and to test possible therapeutic strategies, we generated a mutant AQP2 (763-772 del) knockin mouse. Heterozygous knockin mice showed a severely impaired urine-concentrating ability. However, they were able to slightly increase urine osmolality after dehydration. This milder phenotype, when compared with autosomal-recessive NDI, is a feature of AD-NDI in humans, thus suggesting successful establishment of an AD-NDI mouse model. Immunofluorescence of collecting duct cells in the AD-NDI mouse revealed that the mutant AQP2 was missorted to the basolateral instead of apical plasma membrane. Furthermore, the mutant AQP2 formed a heterooligomer with wild-type AQP2 and showed a dominant-negative effect on the normal apical sorting of wild-type AQP2 even under dehydration. Using this knockin mouse, we tested several drugs for treatment of AD-NDI and found that rolipram, a phosphodiesterase 4 inhibitor, was able to increase urine osmolality. Phosphodiesterase inhibitors may thus be useful drugs for the treatment of AD-NDI. This animal model demonstrates that a mutant monomer gains a dominant-negative effect that reverses the normal polarized sorting of multimers.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.forename: Keiko
authors.initials: K
authors.lastname: Uchida
authors.forename: Kosaku
authors.initials: K
authors.lastname: Nitta
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horita
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ohno
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics* / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004252:DNA Mutational Analysis; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D016368:Frameshift Mutation; D005799:Genes, Dominant; D006801:Humans; D007671:Kidney Concentrating Ability / Q000187:drug effects / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009994:Osmolar Concentration; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D021381:Protein Transport; D020889:Rolipram / Q000627:therapeutic use*; D014556:Urine / Q000737:chemistry
chemical_list: D051399:Aquaporin 2; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram