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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Nitta, Kosaku Rai, Tatemitsu Uchida, Keiko Sasaki, Sei Yang, Sung-sen Ohno, Mayuko Harada, Akihiro Uchida, Shinichi Horita, Shigeru Sohara, Eisei |
| Description | Author Affiliation: Sohara E ( Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 38 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Aquaporin 2 Genetics Diabetes Insipidus, Nephrogenic Drug Therapy Frameshift Mutation Genes, Dominant Rolipram Therapeutic Use 3',5'-Cyclic-AMP Phosphodiesterases Antagonists & Inhibitors Animals Metabolism Cyclic Nucleotide Phosphodiesterases, Type 4 DNA Mutational Analysis Physiopathology Disease Models, Animal Kidney Concentrating Ability Drug Effects Physiology Kidney Tubules, Collecting Cytology Mice Mice, Inbred C57BL Mice, Transgenic Osmolar Concentration Phosphodiesterase Inhibitors Protein Transport Urine Chemistry Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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