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

doi:10.1073/pnas.0602331103

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

*Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan;
^†Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; and
^‡Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Shouwamachi, Maebashi, Gunma 371-8512, Japan

Edited by Maurice B. Burg, National Institutes of Health, Bethesda, MD, and approved July 28, 2006 (received for review March 22, 2006)

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.

Footnotes

^§To whom correspondence should be addressed. E-mail: suchida.kid{at}tmd.ac.jp
Author contributions: S.S. and S.U. designed research; E.S., T.R., S.-S.Y., K.U., K.N., S.H., and M.O. performed research; and A.H. contributed new reagents/analytic tools.
The authors declare no conflict of interest.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

AD,

autosomal-dominant;

NDI,

nephrogenic diabetes insipidus;

AQP2,

aquaporin 2;

PDE,

phosphodiesterase;

dDAVP,

1-deamino-8-d-arginine vasopressin.