Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation

Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14217-22. doi: 10.1073/pnas.0602331103. Epub 2006 Sep 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • Animals
  • Aquaporin 2 / genetics*
  • Aquaporin 2 / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • DNA Mutational Analysis
  • Diabetes Insipidus, Nephrogenic / drug therapy*
  • Diabetes Insipidus, Nephrogenic / genetics*
  • Diabetes Insipidus, Nephrogenic / physiopathology
  • Disease Models, Animal
  • Female
  • Frameshift Mutation*
  • Genes, Dominant*
  • Humans
  • Kidney Concentrating Ability / drug effects
  • Kidney Concentrating Ability / physiology
  • Kidney Tubules, Collecting / cytology
  • Kidney Tubules, Collecting / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Osmolar Concentration
  • Phosphodiesterase Inhibitors / therapeutic use
  • Protein Transport
  • Rolipram / therapeutic use*
  • Urine / chemistry


  • Aquaporin 2
  • Phosphodiesterase Inhibitors
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram