Mouse model of inducible nephrogenic diabetes insipidus produced by floxed aquaporin-2 gene deletion.
Transgenic mouse models of defective urinary concentrating ability produced by deletion of various membrane transport or receptor proteins, including aquaporin-2 (AQP2), are associated with neonatal mortality from polyuria. Here, we report an inducible mouse model of AQP2 gene deletion with severe polyuria in adult mice. LoxP sequences were inserted into introns 1 and 2 in the mouse AQP2 gene by homologous recombination in embryonic stem cells. Mating of germ-line AQP2-loxP mice with tamoxifen-inducible Cre-expressing mice produced offspring with inducible homozygous Cre-AQP2-loxP, which had a normal phenotype. Tamoxifen injections over 10 days resulted in AQP2 gene excision, with undetectable full-length AQP2 transcript in kidney and a >95% reduction in immunoreactive AQP2 protein. Urine osmolality decreased from approximately 2,000 to <500 mosmol/kgH(2)O after 4-5 days, with urine output increasing from 2 to 25 ml/day. Urine osmolality did not increase after water deprivation. Interestingly, AQP3 protein expression in the collecting duct was increased by about fivefold after AQP2 gene excision. Mild renal damage was seen after 6 wk of polyuria, with collecting duct dilatation, yet normal creatinine clearance and serum chemistries. These results establish the first adult model of nephrogenic diabetes insipidus (NDI) caused by AQP2 deficiency, with daily urine output comparable to body weight, although remarkable preservation of renal function compared with non-inducible NDI models.
Yang
Baoxue
B
Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94143-0521, USA. byang@itsa.ucsf.edu
Zhao
Dan
D
Qian
Liman
L
Verkman
A S
AS
D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics* / Q000502:physiology*; D051400:Aquaporin 3 / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000209:etiology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007671:Kidney Concentrating Ability / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011141:Polyuria / Q000503:physiopathology
D051399:Aquaporin 2; D051400:Aquaporin 3