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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
38
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pubmed:dateCreated |
2006-9-20
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pubmed:abstractText |
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.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-11035038,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-11181969,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-11389828,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-11536078,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-11929850,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-12539048,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-12787389,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-14662748,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-1652209,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-16581908,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-16641100,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-7311993,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-7532304,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-7541941,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-8140421,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-8429910,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-9268708,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-9649557,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16968783-9729503
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
103
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
14217-22
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:16968783-3',5'-Cyclic-AMP Phosphodiesterases,
pubmed-meshheading:16968783-Animals,
pubmed-meshheading:16968783-Aquaporin 2,
pubmed-meshheading:16968783-Cyclic Nucleotide Phosphodiesterases, Type 4,
pubmed-meshheading:16968783-DNA Mutational Analysis,
pubmed-meshheading:16968783-Diabetes Insipidus, Nephrogenic,
pubmed-meshheading:16968783-Disease Models, Animal,
pubmed-meshheading:16968783-Female,
pubmed-meshheading:16968783-Frameshift Mutation,
pubmed-meshheading:16968783-Genes, Dominant,
pubmed-meshheading:16968783-Humans,
pubmed-meshheading:16968783-Kidney Concentrating Ability,
pubmed-meshheading:16968783-Kidney Tubules, Collecting,
pubmed-meshheading:16968783-Male,
pubmed-meshheading:16968783-Mice,
pubmed-meshheading:16968783-Mice, Inbred C57BL,
pubmed-meshheading:16968783-Mice, Transgenic,
pubmed-meshheading:16968783-Osmolar Concentration,
pubmed-meshheading:16968783-Phosphodiesterase Inhibitors,
pubmed-meshheading:16968783-Protein Transport,
pubmed-meshheading:16968783-Rolipram,
pubmed-meshheading:16968783-Urine
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pubmed:year |
2006
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pubmed:articleTitle |
Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation.
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pubmed:affiliation |
Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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