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Hsp90 inhibitor partially corrects nephrogenic diabetes insipidus in a conditional knock-in mouse model of aquaporin-2 mutation

Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California, USA

¹ Correspondence: Department of Medicine, 1246 Health Sciences East Tower, Box 0521, University of California, San Francisco, CA 94143-0521, USA. E-mail: baoxue.yang{at}ucsf.edu

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.—Yang, B., Zhao, D., Verkman, A. S. Hsp90 inhibitor partially corrects nephrogenic diabetes insipidus in a conditional knock-in mouse model of aquaporin-2 mutation.

Key Words: AQP2 • water transport • water channel • transgenic mouse • NDI • polyuria

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				A. S. Verkman Aquaporins: translating bench research to human disease J. Exp. Biol., June 1, 2009; 212(11): 1707 - 1715. [Abstract] [Full Text] [PDF]