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

• DOI: 10.1073/pnas.0602331103
• Publication Date: 2006-09-13T02:25:03Z
• Authors: Eisei Sohara; Tatemitsu Rai; Sung-Sen Yang; Keiko Uchida; Kosaku Nitta; Shigeru Horita; Mayuko Ohno; Akihiro Harada; Sei Sasaki; Shinichi Uchida
• Keywords: Nephrogenic diabetes insipidus; Aquaporin 2; Compound heterozygosity

Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify molecular mechanism(s) this disease in vivo and to test possible therapeutic strategies, we generated a mutant AQP2 (763–772 del) knockin mouse. Heterozygous mice showed severely impaired urine-concentrating ability. However, they were able slightly increase urine osmolality after dehydration. This milder phenotype, when compared with autosomal-recessive NDI, is feature AD-NDI humans, thus suggesting successful establishment an mouse model. Immunofluorescence collecting duct cells revealed that was missorted basolateral instead apical plasma membrane. Furthermore, formed heterooligomer wild-type dominant-negative effect on normal sorting even under Using mouse, tested several drugs for treatment found rolipram, phosphodiesterase 4 inhibitor, osmolality. Phosphodiesterase inhibitors may be useful AD-NDI. animal model demonstrates monomer gains reverses polarized multimers.