Diabetes Insipidus in Mice with a Mutation in Aquaporin-2

Overview

Journal PLoS Genet

Specialty Genetics

Date 2005 Aug 27

PMID 16121255

Citations 29

Authors

David J Lloyd

Frank Wesley Hall

Lisa M Tarantino

Nicholas Gekakis

Affiliations

Soon will be listed here.

Abstract

Congenital nephrogenic diabetes insipidus (NDI) is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI.

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References

Ma T, Song Y, Yang B, Gillespie A, Carlson E, Epstein C . Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc Natl Acad Sci U S A. 2000; 97(8):4386-91. PMC: 18251. DOI: 10.1073/pnas.080499597. View

Tamarappoo B, Verkman A . Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest. 1998; 101(10):2257-67. PMC: 508814. DOI: 10.1172/JCI2303. View

Yang B, Ma T, Verkman A . Erythrocyte water permeability and renal function in double knockout mice lacking aquaporin-1 and aquaporin-3. J Biol Chem. 2000; 276(1):624-8. DOI: 10.1074/jbc.M008664200. View

Yang B, Gillespie A, Carlson E, Epstein C, Verkman A . Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem. 2000; 276(4):2775-9. DOI: 10.1074/jbc.M008216200. View

Matsumura Y, Uchida S, Kondo Y, Miyazaki H, Ko S, Hayama A . Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nat Genet. 1999; 21(1):95-8. DOI: 10.1038/5036. View

De Mattia F, Savelkoul P, Bichet D, Kamsteeg E, Konings I, Marr N . A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L. Hum Mol Genet. 2004; 13(24):3045-56. DOI: 10.1093/hmg/ddh339. View

Nelms K, Goodnow C . Genome-wide ENU mutagenesis to reveal immune regulators. Immunity. 2001; 15(3):409-18. DOI: 10.1016/s1074-7613(01)00199-6. View

Knoers N, Deen P . Molecular and cellular defects in nephrogenic diabetes insipidus. Pediatr Nephrol. 2002; 16(12):1146-52. DOI: 10.1007/s004670100051. View

Marr N, Bichet D, Lonergan M, Arthus M, Jeck N, Seyberth H . Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus. Hum Mol Genet. 2002; 11(7):779-89. DOI: 10.1093/hmg/11.7.779. View

10.

Dempski Jr R, Imperiali B . Oligosaccharyl transferase: gatekeeper to the secretory pathway. Curr Opin Chem Biol. 2002; 6(6):844-50. DOI: 10.1016/s1367-5931(02)00390-3. View

11.

Maghnie M . Diabetes insipidus. Horm Res. 2003; 59 Suppl 1:42-54. DOI: 10.1159/000067844. View

12.

Asai T, Kuwahara M, Kurihara H, Sakai T, Terada Y, Marumo F . Pathogenesis of nephrogenic diabetes insipidus by aquaporin-2 C-terminus mutations. Kidney Int. 2003; 64(1):2-10. DOI: 10.1046/j.1523-1755.2003.00049.x. View

13.

Kamsteeg E, Bichet D, Konings I, Nivet H, Lonergan M, Arthus M . Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus. J Cell Biol. 2003; 163(5):1099-109. PMC: 2173618. DOI: 10.1083/jcb.200309017. View

14.

Hendriks G, Koudijs M, van Balkom B, Oorschot V, Klumperman J, Deen P . Glycosylation is important for cell surface expression of the water channel aquaporin-2 but is not essential for tetramerization in the endoplasmic reticulum. J Biol Chem. 2003; 279(4):2975-83. DOI: 10.1074/jbc.M310767200. View

15.

Wen B, Pletcher M, Warashina M, Choe S, Ziaee N, Wiltshire T . Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity. Proc Natl Acad Sci U S A. 2004; 101(15):5604-9. PMC: 397439. DOI: 10.1073/pnas.0306907101. View

16.

King L, Kozono D, Agre P . From structure to disease: the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol. 2004; 5(9):687-98. DOI: 10.1038/nrm1469. View

17.

Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S . Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature. 1993; 361(6412):549-52. DOI: 10.1038/361549a0. View

18.

van den Ouweland A, Dreesen J, Verdijk M, Knoers N, Monnens L, Rocchi M . Mutations in the vasopressin type 2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus. Nat Genet. 1992; 2(2):99-102. DOI: 10.1038/ng1092-99. View

19.

Deen P, Verdijk M, Knoers N, Wieringa B, Monnens L, Van Os C . Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science. 1994; 264(5155):92-5. DOI: 10.1126/science.8140421. View

20.

Ishibashi K, Sasaki S, Fushimi K, Uchida S, Kuwahara M, Saito H . Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells. Proc Natl Acad Sci U S A. 1994; 91(14):6269-73. PMC: 44182. DOI: 10.1073/pnas.91.14.6269. View