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The Journal of Membrane Biology

, Volume 246, Issue 4, pp 297–305 | Cite as

What Do Aquaporin Knockout Studies Tell Us about Fluid Transport in Epithelia?

  • Oliver J. MaclarenEmail author
  • James Sneyd
  • Edmund J. Crampin
Article

Abstract

The investigation of near-isosmotic water transport in epithelia goes back over 100 years; however, debates over mechanism and pathway remain. Aquaporin (AQP) knockouts have been used by various research groups to test the hypothesis of an osmotic mechanism as well as to explore the paracellular versus transcellular pathway debate. Nonproportional reductions in the water permeability of a water-transporting epithelial cell (e.g., a reduction of around 80–90 %) compared to the reduction in overall water transport rate in the knockout animal (e.g., a reduction of 50–60 %) are commonly found. This nonproportionality has led to controversy over whether AQP knockout studies support or contradict the osmotic mechanism. Arguments raised for and against an interpretation supporting the osmotic mechanism typically have partially specified, implicit, or incorrect assumptions. We present a simple mathematical model of the osmotic mechanism with clear assumptions and, for models based on this mechanism, establish a baseline prediction of AQP knockout studies. We allow for deviations from isotonic/isosmotic conditions and utilize dimensional analysis to reduce the number of parameters that must be considered independently. This enables a single prediction curve to be used for multiple epithelial systems. We find that a simple, transcellular-only osmotic mechanism sufficiently predicts the results of knockout studies and find criticisms of this mechanism to be overstated. We note, however, that AQP knockout studies do not give sufficient information to definitively rule out an additional paracellular pathway.

Keywords

Aquaporin knockout Epithelial transport Osmosis Aquaporins Water transport Osmotic mechanism 

Notes

Acknowledgments

O. J. M. was supported by the New Zealand Tertiary Education Commission’s Top Achiever Doctoral Scholarship. This work was supported by NIH Grant R01 DE19245-01.

References

  1. Agre P (2004) Aquaporin water channels (Nobel lecture). Angew Chem Int Ed Engl 43(33):4278–4290PubMedCrossRefGoogle Scholar
  2. Buckingham E (1914) On physically similar systems; illustrations of the use of dimensional equations. Phys Rev 4(4):345–376CrossRefGoogle Scholar
  3. Curran PF (1960) Na, Cl, and water transport by rat ileum in vitro. J Gen Physiol 43:1137–1148PubMedCrossRefGoogle Scholar
  4. Diamond J, Bossert W (1967) Standing-gradient osmotic flow a mechanism for coupling of water and solute transport in epithelia. J Gen Physiol 50(8):2061–2083PubMedCrossRefGoogle Scholar
  5. Finkelstein A (1987) Water movement through lipid bilayers, pores, and plasma membranes: theory and reality, vol 4. Wiley, New YorkGoogle Scholar
  6. Fischbarg J (2010) Fluid transport across leaky epithelia: central role of the tight junction and supporting role of aquaporins. Physiol Rev 90:1271–1290PubMedCrossRefGoogle Scholar
  7. Friedman M (2008) Principles and models of biological transport. Springer, New YorkCrossRefGoogle Scholar
  8. Gin E, Crampin EJ, Brown DA, Shuttleworth TJ, Yule DI, Sneyd J (2007) A mathematical model of fluid secretion from a parotid acinar cells. J Theor Biol 248:64–80PubMedCrossRefGoogle Scholar
  9. Hill AE (2008) Fluid transport: a guide for the perplexed. J Membr Biol 223(1):1–11PubMedCrossRefGoogle Scholar
  10. Hill AE, Shachar-Hill B, Shachar-Hill Y (2004) What are aquaporins for? J Membr Biol 197:1–32PubMedCrossRefGoogle Scholar
  11. Kedem O, Katchalsky A (1958) Thermodynamic analysis of the permeability of biological membranes to non-electrolytes. Biochim Biophys Acta 27:229–246PubMedCrossRefGoogle Scholar
  12. 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
  13. Logan D (1997) Applied mathematics. Wiley, New YorkGoogle Scholar
  14. 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(8):4296–4299PubMedCrossRefGoogle Scholar
  15. 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(29):20071–20074PubMedCrossRefGoogle Scholar
  16. Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS (2000) Lung fluid transport in aquaporin-5 knockout mice. J Clin Invest 105(1):93–100PubMedCrossRefGoogle Scholar
  17. Maclaren OJ, Sneyd J, Crampin EJ (2012) Efficiency of primary saliva secretion: an analysis of parameter dependence in dynamic single-cell and acinus models, with application to aquaporin knockout studies. J Membr Biol 245:29–50PubMedCrossRefGoogle Scholar
  18. Mathias RT, Wang H (2005) Local osmosis and isotonic transport. J Membr Biol 208:39–53PubMedCrossRefGoogle Scholar
  19. O’Brien S (2011) Lin & Segel’s standing gradient problem revisited: a lesson in mathematical modeling and asymptotics. SIAM Rev 53(4):775–796CrossRefGoogle Scholar
  20. Palk L, Sneyd J, Shuttleworth TJ, Yule DI, Crampin EJ (2010) A dynamic model of saliva secretion. J Theor Biol 266(4):625–640PubMedCrossRefGoogle Scholar
  21. Reuss L (2009) Water transport by epithelia. Wiley, HobokenGoogle Scholar
  22. Reuss L (2010) Epithelial transport. Wiley, HobokenGoogle Scholar
  23. 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(16):9660–9664PubMedCrossRefGoogle Scholar
  24. Segel L (1970) Standing-gradient flows driven by active solute transport. J Theor Biol 29(2):233–250PubMedCrossRefGoogle Scholar
  25. Spring KR (1998) Routes and mechanism of fluid transport by epithelia. Annu Rev Physiol 60:105–119PubMedCrossRefGoogle Scholar
  26. Spring KR (1999) Epithelial fluid transport—a century of investigation. News Physiol Sci 14(3):92–98PubMedGoogle Scholar
  27. Vallon V, Verkman AS, Schnermann J (2000) Luminal hypotonicity in proximal tubules of aquaporin-1-knockout mice. Am J Physiol Renal Physiol 278(6):F1030–F1033PubMedGoogle Scholar
  28. Verkman AS (2011) Aquaporins at a glance. J Cell Sci 124(Pt 13):2107–2112PubMedCrossRefGoogle Scholar
  29. Weinstein AM (1994) Mathematical models of tubular transport. Annu Rev Physiol 56:691–709PubMedCrossRefGoogle Scholar
  30. Weinstein AM (2003) Mathematical models of renal fluid and electrolyte transport: acknowledging our uncertainty. Am J Physiol Renal Physiol 284(5):F871–F884PubMedGoogle Scholar
  31. Weinstein A, Stephenson J (1981) Models of coupled salt and water transport across leaky epithelia. J Membr Biol 60(1):1–20PubMedCrossRefGoogle Scholar
  32. Weinstein A, Stephenson J, Spring K (1981) The coupled transport of water. In: Bonting SL, de Pont JJHHM (eds) New comprehensive biochemistry. Membrane transport. Elsevier, Amsterdam, pp 311–351Google Scholar
  33. Whittembury G, Reuss L (1992) Mechanisms of coupling of solute and solvent transport in epithelia. Raven Press, New YorkGoogle Scholar
  34. Zeuthen T (2010) Water-transporting proteins. J Membr Biol 234:57–73PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Oliver J. Maclaren
    • 1
    Email author
  • James Sneyd
    • 2
  • Edmund J. Crampin
    • 1
    • 3
  1. 1.Auckland Bioengineering InstituteThe University of AucklandAucklandNew Zealand
  2. 2.Department of MathematicsThe University of AucklandAucklandNew Zealand
  3. 3.Department of Engineering ScienceThe University of AucklandAucklandNew Zealand

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