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

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. FASEB J. 23, 503‐512 (2009)