rdf:type |
|
lifeskim:mentions |
umls-concept:C0025914,
umls-concept:C0026336,
umls-concept:C0026809,
umls-concept:C0026882,
umls-concept:C0162283,
umls-concept:C0213238,
umls-concept:C0243044,
umls-concept:C0719517,
umls-concept:C1517676,
umls-concept:C1701901,
umls-concept:C1825534,
umls-concept:C1999216,
umls-concept:C2349182
|
pubmed:issue |
2
|
pubmed:dateCreated |
2009-1-30
|
pubmed:abstractText |
Mutations in aquaporin-2 (AQP2) that interfere with its cellular processing can produce autosomal recessive nephrogenic diabetes insipidus (NDI). Prior gene knock-in of the human NDI-causing AQP2 mutation T126M produced mutant mice that died by age 7 days. Here, we used a novel "conditional gene knock-in" strategy to generate adult, AQP2-T126M mutant mice. Mice separately heterozygous for floxed wild-type AQP2 and AQP2-T126M were bred to produce hemizygous mice, which following excision of the wild-type AQP2 gene by tamoxifen-induced Cre-recombinase gave AQP2(T126M/-) mice. AQP2(T126M/-) mice were polyuric (9-14 ml urine/day) compared to AQP2(+/+) mice (1.6 ml/day) and had reduced urine osmolality (400 vs. 1800 mosmol). Kidneys of AQP2(T126M/-) mice expressed core-glycosylated AQP2-T126M protein in an endoplasmic reticulum pattern. Screening of candidate protein folding "correctors" in AQP2-T126M-transfected kidney cells showed increased AQP2-T126M plasma membrane expression with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG increased urine osmolality in AQP2(T126M/-) mice by >300 mosmol but had no effect in AQP2(-/-) mice. Kidneys of 17-AAG-treated AQP2(T126M/-) mice showed partial rescue of defective AQP2-T126M cellular processing. Our results establish an adult mouse model of NDI and demonstrate partial restoration of urinary concentration function by a compound currently in clinical trials for other indications.
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pubmed:grant |
|
pubmed:commentsCorrections |
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http://linkedlifedata.com/resource/pubmed/commentcorrection/18854434-9745427
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pubmed:language |
eng
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pubmed:journal |
|
pubmed:citationSubset |
IM
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pubmed:chemical |
|
pubmed:status |
MEDLINE
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pubmed:month |
Feb
|
pubmed:issn |
1530-6860
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pubmed:author |
|
pubmed:issnType |
Electronic
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pubmed:volume |
23
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
|
pubmed:pagination |
503-12
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pubmed:dateRevised |
2010-9-21
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pubmed:meshHeading |
pubmed-meshheading:18854434-Aging,
pubmed-meshheading:18854434-Animals,
pubmed-meshheading:18854434-Aquaporin 2,
pubmed-meshheading:18854434-Base Sequence,
pubmed-meshheading:18854434-Cell Line,
pubmed-meshheading:18854434-Diabetes Insipidus, Nephrogenic,
pubmed-meshheading:18854434-Disease Models, Animal,
pubmed-meshheading:18854434-Dogs,
pubmed-meshheading:18854434-Gene Knock-In Techniques,
pubmed-meshheading:18854434-HSP90 Heat-Shock Proteins,
pubmed-meshheading:18854434-Mice,
pubmed-meshheading:18854434-Mice, Transgenic,
pubmed-meshheading:18854434-Mutation
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pubmed:year |
2009
|