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

Proceedings of the National Academy of Sciences of the United States of America - Tập 103 Số 38 - Trang 14217-14222 - 2006
Eisei Sohara1, Tatemitsu Rai1, Sung‐Sen Yang1, Keiko Uchida2, Kosaku Nitta2, Shigeru Horita2, Mayuko Ohno2, Akihiro Harada3, Sei Sasaki1, Shinichi Uchida1
1Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo, Tokyo 113-8519, Japan
2Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; and
3Laboratory 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

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

10.1038/361549a0

10.1152/ajprenal.1998.275.3.F328

10.1073/pnas.92.4.1013

10.1152/ajpcell.1995.268.6.C1546

10.1126/science.8140421

10.1172/JCI2605

10.1086/323643

10.1046/j.1523-1755.2003.00049.x

10.1006/bbrc.1997.7111

10.1074/jbc.M008216200

10.1152/ajprenal.00337.2004

S Homma, SM Gapstur, A Coffey, H Valtin, TP Dousa Am J Physiol 261, F345–F353 (1991).

10.1073/pnas.0600895103

10.1073/pnas.0511324103

10.1146/annurev.physiol.63.1.607

10.1016/S0092-8674(01)00371-3

10.1038/ng1082

10.1093/hmg/11.7.779

10.1083/jcb.200309017

10.1056/NEJM198112243052601

10.1152/ajprenal.00040.2002

10.1371/journal.pgen.0010020

10.1152/ajprenal.00494.2005

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 103 Số 38

14217-14222

Thông tin tác giả