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

作者：Yang Baoxue^*; Zhao Dan; Verkman A S

来源：The FASEB Journal, 2009, 23(2): 503-512.

DOI：10.1096/fj.08-118422

• AQP2
• water transport
• water channel
• transgenic mouse
• NDI
• polyuria

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)

• 出版日期2009-2