Advertisement

Novel roles of aquaporins revealed by phenotype analysis of knockout mice

  • A. S. Verkman
Chapter
Part of the Reviews of Physiology, Biochemistry, and Pharmacology book series (REVIEWS, volume 155)

Abstract

The aquaporins (AQPs) are small integral membrane proteins that transport water and in some cases small solutes such as glycerol. Physiological roles of the ten or more mammalian AQPs have been proposed based on their expression in epithelial, endothelial and other tissues, their regulation, and in some cases the existence of humans with AQP mutation. Here, the role of AQPs in mammalian physiology is reviewed, based on phenotype analysis of transgenic mouse models of AQP deletion/mutation. Phenotype studies support the predicted roles of AQPs in kidney tubule and microvessel fluid transport for urinary concentrating function, and in fluid-secreting glandular epithelia. The phenotype studies have also shown unexpected roles of AQPs in brain and corneal swelling, in neural signal transduction, in regulation of intracranial and intraocular pressure, and in tumor angiogenesis and cell migration. The water/glycerol-transporting AQPs were found to play unexpected roles in skin hydration and in fat metabolism. However, many phenotype studies were negative, such as normal airway/lung and skeletal muscle function, despite AQP expression, indicating that tissue-specific AQP expression does not indicate physiological significance. The mouse phenotype data suggest that modulators of AQP expression/function may have such wide-ranging clinical applications as diuretics and in the treatment of brain swelling, glaucoma, epilepsy, obesity, and cancer.

Keywords

Null Mouse Nephrogenic Diabetes Insipidus Wildtype Mouse Submucosal Gland Airway Surface Liquid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, Engel A, Nielsen S (2002) Aquaporin water channels—from atomic structure to clinical medicine. J Physiol 542:3–16PubMedCrossRefGoogle Scholar
  2. Amiry-Moghaddam M, Otsuka T, Hurn PD, Traystman RJ, Haug FM, Froehner SC, Adams ME, Neely JD, Agre P, Ottersen OP, Bhardwaj A (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci USA 100:2106–2111PubMedCrossRefGoogle Scholar
  3. Amiry-Moghaddam M, Williamson A, Palomba M, Eid T, de Lanerolle NC, Nagelhus EA, Adams ME, Froehner SC, Agre P, Ottersen OP (2003) Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci USA 100:13615–13620PubMedCrossRefGoogle Scholar
  4. Bai C, Fukuda N, Song Y, Ma T, Matthay MA, Verkman AS (1999) Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice. J Clin Invest 103:555–561PubMedGoogle Scholar
  5. Berry V, Francis P, Kaushal S, Moore A, Bhattacharya S (2000) Missense mutations in MIP underlie autosomal dominant ‘polymorphic’ and lamellar cataracts linked to 12q. Nat Genet 25:15–17PubMedCrossRefGoogle Scholar
  6. Binder DK, Oshio K, Ma T, Verkman AS, Manley GT (2004) Increased seizure threshold in mice lacking aquaporin-4 water channels. Neuroreport 15:259–262PubMedCrossRefGoogle Scholar
  7. Binder DK, Papadopoulos MC, Haggie PM, Verkman AS (2004) In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J Neurosci 24:8049–8056PubMedCrossRefGoogle Scholar
  8. Chou CL, Ma T, Yang B, Knepper MA, Verkman AS (1998) Fourfold reduction of water permeability in inner medullary collecting duct of aquaporin-4 knockout mice. Am J Physiol 274:C549–C554PubMedGoogle Scholar
  9. Chou CL, Knepper MA, Hoek AN, Brown D, Yang B, Ma T, Verkman AS (1999) Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaporin-1 null mice. J Clin Invest 103:491–496PubMedGoogle Scholar
  10. Condeelis J (1993) Life at the leading edge: the formation of cell protrusions. Annu Rev Cell Biol 9:411–444PubMedCrossRefGoogle Scholar
  11. Da T, Verkman AS (2004) Aquaporin-4 gene disruption in mice protects against impaired retinal function and cell death after ischemia. Invest Ophthalmol Vis Sci 45:4477–4483PubMedCrossRefGoogle Scholar
  12. Deen PM, Verdijk MA, Knoers NV, Wieringa B, Monnens LA, van Os CH, van Oost BA (1994) Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264:92–95PubMedGoogle Scholar
  13. Elkjaer ML, Nejsum LN, Gresz V, Kwon TH, Jensen UB, Frokiaer J, Nielsen S (2001) Immunolocalization of aquaporin-8 in rat kidney, gastrointestinal tract, testis, and airways. Am J Physiol Renal Physiol 281:F1047–F1057PubMedGoogle Scholar
  14. Endo M, Jain RK, Witwer B, Brown D (1999) Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas. Microvasc Res 58:89–98PubMedCrossRefGoogle Scholar
  15. Fang X, Yang B, Matthay MA, Verkman AS (2002) Evidence against aquaporin-1-dependent CO2 permeability in lung and kidney. J Physiol 542:63–69PubMedCrossRefGoogle Scholar
  16. Frigeri A, Gropper MA, Umenishi F, Kawashima M, Brown D, Verkman AS (1995) Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues. J Cell Sci 108:2993–3002PubMedGoogle Scholar
  17. Fujiyoshi Y, Mitsuoka K, de Groot BL, Philippsen A, Grubmuller H, Agre P, Engel A (2002) Structure and function of water channels. Curr Opin Struct Biol 12:509–515PubMedCrossRefGoogle Scholar
  18. Hara M, Verkman AS (2003) Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice. Proc Natl Acad Sci USA 100:7360–7365PubMedCrossRefGoogle Scholar
  19. Hara M, Ma T, Verkman AS (2002) Selectively reduced glycerol in skin of aquaporin-3-deficient mice may account for impaired skin hydration, elasticity, and barrier recovery. J Biol Chem 277:46616–46621PubMedCrossRefGoogle Scholar
  20. Hara-Chikuma M, Sohara E, Rai T, Ikawa M, Okabe M, Sasaki S, Uchida S, Verkman AS (2005) Progressive adipocyte hypertrophy in aquaporin-7 deficient mice: adipocyte glycerol permeability as a novel regulator of fat accumulation. J Biol Chem 280:15493–15496PubMedCrossRefGoogle Scholar
  21. Jayaraman S, Song Y, Vetrivel L, Shankar L, Verkman AS (2001) Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J Clin Invest 107:317–324PubMedGoogle Scholar
  22. King LS, Choi M, Fernandez PC, Cartron JP, Agre P (2001) Defective urinary-concentrating ability due to a complete deficiency of aquaporin-1. N Engl J Med 345:175–179PubMedCrossRefGoogle Scholar
  23. Krane CM, Fortner CN, Hand AR, McGraw DW, Lorenz JN, Wert SE, Towne JE, Paul RJ, Whitsett JA, Menon AG (2001) Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation. Proc Natl Acad Sci USA 98:14114–14119PubMedCrossRefGoogle Scholar
  24. Krane CM, Melvin JE, Nguyen HV, Richardson L, Towne JE, Doetschman T, Menon AG (2001) Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation. J Biol Chem 276:23413–23420PubMedCrossRefGoogle Scholar
  25. Kuang K, Yiming M, Wen Q, Li Y, Ma L, Iserovich P, Verkman AS, Fischbarg J (2004) Fluid transport across cultured layers of corneal endothelium from aquaporin-1 null mice. Exp Eye Res 78:791–798PubMedCrossRefGoogle Scholar
  26. Kuriyama H, Kawamoto S, Ishida N, Ohno I, Mita S, Matsuzawa Y, Matsubara K, Okubo K (1997) Molecular cloning and expression of a novel human aquaporin from adipose tissue with glycerol permeability. Biochem Biophys Res Commun 241:53–58PubMedCrossRefGoogle Scholar
  27. Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369PubMedCrossRefGoogle Scholar
  28. Levin MH, Verkman AS (2004) Aquaporin-dependent water permeation at the mouse ocular surface: in vivo microfluorimetric measurements in cornea and conjunctiva. Invest Ophthalmol Vis Sci 45:4423–4432PubMedCrossRefGoogle Scholar
  29. Li J, Verkman AS (2001) Impaired hearing in mice lacking aquaporin-4 water channels. J Biol Chem 276:31233–31237PubMedCrossRefGoogle Scholar
  30. Li J, Patil RV, Verkman AS (2002) Mildly abnormal retinal function in transgenic mice without Muller cell aquaporin-4 water channels. Invest Ophthalmol Vis Sci 43:573–579PubMedGoogle Scholar
  31. Ma T, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (1997) Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J Clin Invest 100:957–962PubMedGoogle Scholar
  32. Ma T, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (1998) Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels. J Biol Chem 273:4296–4299PubMedCrossRefGoogle Scholar
  33. Ma T, Song Y, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (1999) Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J Biol Chem 274:20071–20074PubMedCrossRefGoogle Scholar
  34. Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS (2000) Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest 105:93–100PubMedGoogle Scholar
  35. Ma T, Song Y, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (2000) Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc Natl Acad Sci USA 97:4386–4391PubMedCrossRefGoogle Scholar
  36. Ma T, Jayaraman S, Wang KS, Song Y, Yang B, Li J, Bastidas JA, Verkman AS (2001) Defective dietary fat processing in transgenic mice lacking aquaporin-1 water channels. Am J Physiol Cell Physiol 280:C126–C134PubMedGoogle Scholar
  37. Ma T, Hara M, Sougrat R, Verbavatz JM, Verkman AS (2002) Impaired stratum corneum hydration in mice lacking epidermal water channel aquaporin-3. J Biol Chem 277:17147–17153PubMedCrossRefGoogle Scholar
  38. Maeda N, Funahashi T, Hibuse T, Nagasawa A, Kishida K, Kuriyama H, Nakamura T, Kihara S, Shimomura I, Matsuzawa Y (2004) Adaptation to fasting by glycerol transport through aquaporin 7 in adipose tissue. Proc Natl Acad Sci USA 101:17801–17806PubMedCrossRefGoogle Scholar
  39. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163PubMedCrossRefGoogle Scholar
  40. Mhatre AN, Stern RE, Li J, Lalwani AK (2002) Aquaporin 4 expression in the mammalian inner ear and its role in hearing. Biochem Biophys Res Commun 297:987–996PubMedCrossRefGoogle Scholar
  41. Moore M, Ma T, Yang B, Verkman AS (2000) Tear secretion by lacrimal glands in transgenic mice lacking water channels AQP1, AQP3, AQP4 and AQP5. Exp Eye Res 70:557–562PubMedCrossRefGoogle Scholar
  42. Nico B, Frigeri A, Nicchia GP, Corsi P, Ribatti D, Quondamatteo F, Herken R, Girolamo F, Marzullo A, Svelto M, Roncali L (2003) Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. Glia 42:235–251PubMedCrossRefGoogle Scholar
  43. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180PubMedGoogle Scholar
  44. Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel aquaporin-1. FASEB J 19:76–78PubMedGoogle Scholar
  45. Pallone TL, Edwards A, Ma T, Silldorff EP, Verkman AS (2000) Requirement of aquaporin-1 for NaCl-driven water transport across descending vasa recta. J Clin Invest 105:215–222PubMedCrossRefGoogle Scholar
  46. Papadopoulos MC, Verkman AS (2005) Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem 280:13906–13912PubMedCrossRefGoogle Scholar
  47. Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18:1291–1293PubMedGoogle Scholar
  48. Papadopoulos MC, Binder DK, Verkman AS (2005) Enhanced macromolecular diffusion in brain extracellular space in mouse models of vasogenic edema measured by cortical surface photobleaching. FASEB J 19:425–427PubMedGoogle Scholar
  49. Rash JE, Yasumura T, Hudson CS, Agre P, Nielsen S (1998) Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc Natl Acad Sci USA 95:11981–11986PubMedCrossRefGoogle Scholar
  50. Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS (2005) Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434:786–792PubMedCrossRefGoogle Scholar
  51. Schnermann J, Chou CL, Ma T, Traynor T, Knepper MA, Verkman AS (1998) Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc Natl Acad Sci USA 95:9660–9664PubMedCrossRefGoogle Scholar
  52. Solenov E, Watanabe H, Manley GT, Verkman AS (2004) Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am J Physiol Cell Physiol 286:C426–C432PubMedCrossRefGoogle Scholar
  53. Song Y, Verkman AS (2001) Aquaporin-5 dependent fluid secretion in airway submucosal glands. J Biol Chem 276:41288–41292PubMedCrossRefGoogle Scholar
  54. Song Y, Fukuda N, Bai C, Ma T, Matthay MA, Verkman AS (2000) Role of aquaporins in alveolar fluid clearance in neonatal and adult lung, and in oedema formation following acute lung injury: studies in transgenic aquaporin null mice. J Physiol 525 (Pt 3):771–779PubMedCrossRefGoogle Scholar
  55. Song Y, Ma T, Matthay MA, Verkman AS (2000) Role of aquaporin-4 in airspace-to-capillary water permeability in intact mouse lung measured by a novel gravimetric method. J Gen Physiol 115:17–27PubMedCrossRefGoogle Scholar
  56. Song Y, Yang B, Matthay MA, Ma T, Verkman AS (2000) Role of aquaporin water channels in pleural fluid dynamics. Am J Physiol Cell Physiol 279:C1744–C1750PubMedGoogle Scholar
  57. Song Y, Jayaraman S, Yang B, Matthay MA, Verkman AS (2001) Role of aquaporin water channels in airway fluid transport, humidification, and surface liquid hydration. J Gen Physiol 117:573–582PubMedCrossRefGoogle Scholar
  58. Song Y, Sonawane N, Verkman AS (2002) Localization of aquaporin-5 in sweat glands and functional analysis using knockout mice. J Physiol 541:561–568PubMedCrossRefGoogle Scholar
  59. Thiagarajah JR, Verkman AS (2002) Aquaporin deletion in mice reduces corneal water permeability and delays restoration of transparency after swelling. J Biol Chem 277:19139–19144PubMedCrossRefGoogle Scholar
  60. Thiagarajah JR, Papadopoulos MC, Verkman AS (2005) Non-invasive early detection of brain edema in mice by near-infrared light scattering. J Neurosci Res 80:293–299PubMedCrossRefGoogle Scholar
  61. Vacca A, Frigeri A, Ribatti D, Nicchia GP, Nico B, Ria R, Svelto M, Dammacco F (2001) Microvessel overexpression of aquaporin 1 parallels bone marrow angiogenesis in patients with active multiple myeloma. Br J Haematol 113:415–421PubMedCrossRefGoogle Scholar
  62. Vajda Z, Pedersen M, Fuchtbauer EM, Wertz K, Stodkilde-Jorgensen H, Sulyok E, Doczi T, Neely JD, Agre P, Frokiaer J, Nielsen S (2002) Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice. Proc Natl Acad Sci USA 99:13131–13136PubMedCrossRefGoogle Scholar
  63. Vallon V, Verkman AS, Schnermann J (2000) Luminal hypotonicity in proximal tubules of aquaporin-1-knockout mice. Am J Physiol Renal Physiol 278:F1030–F1033PubMedGoogle Scholar
  64. Verbavatz JM, Ma T, Gobin R, Verkman AS (1997) Absence of orthogonal arrays in kidney, brain and muscle from transgenic knockout mice lacking water channel aquaporin-4. J Cell Sci 110:2855–2860PubMedGoogle Scholar
  65. Wang KS, Komar AR, Ma T, Filiz F, McLeroy J, Hoda K, Verkman AS, Bastidas JA (2000) Gastric acid secretion in aquaporin-4 knockout mice. Am J Physiol Gastrointest Liver Physiol 279:G448–G453PubMedGoogle Scholar
  66. Wang KS, Ma T, Filiz F, Verkman AS, Bastidas JA (2000) Colon water transport in transgenic mice lacking aquaporin-4 water channels. Am J Physiol Gastrointest Liver Physiol 279:G463–G470PubMedGoogle Scholar
  67. Yang B, Brown D, Verkman AS (1996) The mercurial insensitive water channel (AQP-4) forms orthogonal arrays in stably transfected Chinese hamster ovary cells. J Biol Chem 271:4577–4580PubMedCrossRefGoogle Scholar
  68. Yang B, Folkesson HG, Yang J, Matthay MA, Ma T, Verkman AS (1999) Reduced osmotic water permeability of the peritoneal barrier in aquaporin-1 knockout mice. Am J Physiol 276:C76–C81PubMedGoogle Scholar
  69. Yang B, Fukuda N, van Hoek A, Matthay MA, Ma T, Verkman AS (2000) Carbon dioxide permeability of aquaporin-1 measured in erythrocytes and lung of aquaporin-1 null mice and in reconstituted proteoliposomes. J Biol Chem 275:2686–2692PubMedCrossRefGoogle Scholar
  70. Yang B, Verbavatz JM, Song Y, Vetrivel L, Manley G, Kao WM, Ma T, Verkman AS (2000) Skeletal muscle function and water permeability in aquaporin-4 deficient mice. Am J Physiol Cell Physiol 278:C1108–C1115PubMedGoogle Scholar
  71. Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (2001) Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem 276:2775–2779PubMedCrossRefGoogle Scholar
  72. Yang B, Ma T, Verkman AS (2001) Erythrocyte water permeability and renal function in double knockout mice lacking aquaporin-1 and aquaporin-3. J Biol Chem 276:624–628PubMedCrossRefGoogle Scholar
  73. Yang B, Song Y, Zhao D, Verkman AS (2005) Phenotype analysis of aquaporin-8 null mice. Am J Physiol Cell Physiol 288:C1161–C1170PubMedCrossRefGoogle Scholar
  74. Zhang D, Vetrivel L, Verkman AS (2002) Aquaporin deletion in mice reduces intraocular pressure and aqueous fluid production. J Gen Physiol 119:561–569PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • A. S. Verkman
    • 1
  1. 1.Departments of Medicine and Physiology, Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations