Skip to main content

Advertisement

SpringerLink
Log in

Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The blood-brain barrier (BBB) regulation is characterized by an interplay between endothelial cells, subendothelial basal laminae and astrocytic cells. Astroglial cells are highly polarized by the differentiation of perivascular membrane domains. These domains are characterized by the aggregation of, among other molecules, the water channel protein aquaporin-4 (AQP4), the dystrophin-dystroglycan complex, and the inwardly rectifying potassium channel protein Kir4.1. Normally, this ion channel plays an important role in spatial buffering of extracellular K+ in the central nervous system, which only can be performed due to the non-uniform distribution of Kir4.1 across the surface of the glial cell. In this study, we observed a mislocalization of Kir4.1 in various human brain tumors (low- and high-grade astrocytomas and oligodendrogliomas), suggesting that buffering capacity of glial cells may be compromised, leading to water influx (cytotoxic edema). Interestingly, whereas dystrophin remained regularly restricted at the endfeet membranes in all cases investigated, AQP4 was found to be redistributed only in high-grade astrocytomas, not in low-grade astrocytomas. If the mechanisms of redistribution of AQP4 and Kir4.1 are different in low- and high-grade gliomas, this may suggest that the mechanisms of clustering of AQP4 and Kir4.1 at the glial endfeet membrane domains are also different. The redistribution of AQP4 in glioblastoma cells is discussed as a reaction to the vasogenic edema, as induced by the breakdown of the BBB, to facilitate reabsorption of excess fluid.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. 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 α-syntrophin-null mice. Proc Natl Acad Sci USA 100:13615–13620

    Google Scholar 

  2. Aoki K, Uchihara T, Tsuchiya K, Nakamura A, Ikeda K, Wakayama Y (2003) Enhanced expression of aquaporin 4 in human brain infarction. Acta Neuropathol 106:121–124

    Google Scholar 

  3. Connors NC, Kofuji P (2002) Dystrophin Dp71 is critical for the clustered localization of potassium channels in retinal glial cells. J Neurosci 22:4321–4327

    Google Scholar 

  4. Connors NC, Adams ME, Froehner SC, Kofuji P (2004) The potassium channel Kir4.1 associates with the dystrophin glycoprotein complex via α-syntrophin in glia. J Biol Chem 279:28387–28392

    Google Scholar 

  5. Dalloz C, Sarig R, Fort P, Yaffe D, Bordais A, Pannicke T, Grosche J, Mornet D, Reichenbach A, Sahel J, Nudel U, Rendon A (2003) Targeted inactivation of dystrophin gene product Dp71: phenotypic impact in mouse retina. Hum Mol Genet 12:1543–1554

    Google Scholar 

  6. Ehmsen J, Poon E, Davies K (2002) The dystrophin-associated protein complex. J Cell Sci 115:2801–2803

    CAS  PubMed  Google Scholar 

  7. Gee SH, Montanaro F, Lindenbaum MH, Carbonetto S (1994) Dystroglycan-α: a dystrophin-associated glyoprotein, is a functional agrin receptor. Cell 77:675–686

    Google Scholar 

  8. Guadagno E, Moukhles H (2004) Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4.1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes. Glia 47:138–149

    Google Scholar 

  9. Hatton JD, Sang HU (1990) Orthogonal arrays are absent from the membranes of human glioblastomatous tissues. Acta Anat (Basel) 137:363–366

    Google Scholar 

  10. Higashi K, Fujita A, Inanobe A, Tanemoto M, Doi K, Kubo T, Kurachi Y (2001) An inwardly rectifying K+ channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol 281:C922–C931

    Google Scholar 

  11. Horio Y (2001) Potassium channels of glial cells: distribution and function. Jpn J Pharmacol 87:1–6

    Google Scholar 

  12. Ishii M, Horio Y, Tada Y, Hibino H, Inanobe A, Ito M, Yamada M, Gotow T, Uchiyama Y, Kurachi Y (1997) Expression and clustered distribution of an inwardly rectifying potassium channel, KAB-2/Kir4.1, on mammalian retinal Müller cell membrane: their regulation by insulin and laminin signals. J Neurosci 17:7725–7735

    Google Scholar 

  13. Kalsi AS, Greenwood K, Wilkin G, Butt AM (2004) Kir4.1 expression by astrocytes and oligodendrocytes in CNS white matter: a developmental study in the rat optic nerve. J Anat 204:475–485

    Google Scholar 

  14. Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129:1045–1056

    Google Scholar 

  15. Kofuji P, Ceelen P, Zahs KR, Surbeck LW, Lester HA, Newman EA (2000) Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci 20:5733–5740

    Google Scholar 

  16. Kofuji P, Biedermann B, Siddharthan B, Raap M, Iandiev I, Milenkovic I, Thomzig A, Veh RW, Bringmann A, Reichenbach A (2002) Kir potassioum channel subunit expression in retinal glial cells: implications for spatial potassium buffering. Glia 39:292–303

    Article  PubMed  Google Scholar 

  17. Lee TS, Eid T, Mane S, Kim JH, Spencer DD, Ottersen OP, Lanerolle NC de (2004) Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy. Acta Neuropathol 108:493–502

    Google Scholar 

  18. Leonoudakis D, Conti LR, Anderson S, Radeke CM, McGuire LMM, Adams ME, Froehner SC, Yates JR, Vandenberg CA (2004) Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x) associated proteins. J Biol Chem 279:22331–22346

    Google Scholar 

  19. Li L, Head V, Timpe LC (2001) Identification of an inward rectifier potassium channel gene expressed in mouse cortical astrocytes. Glia 33:57–71

    Google Scholar 

  20. Ljubimova JY, Lakhter AJ, Loksh A, Yong WH, Riedinger MS, Miner JH, Sorokin LM, Ljubimov AV, Black KL (2001) Overexpression of α4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Cancer Res 61:5601–5610

    Google Scholar 

  21. Nagelhus EA, Horio Y, Inanobe A, Fujita A, Haug FM, Nielsen S, Kurachi Y, Ottersen OP (1999) Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26:47–54

    Article  CAS  PubMed  Google Scholar 

  22. Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquapoprin-4 in the central nervous system: cellular and subcellular distribution and coexpression with Kir4.1. Neuroscience 129:905–913

    Google Scholar 

  23. Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME (2001) Syntrophin-dependent expression and localization of aquaporin-4 water channel protein. Proc Natl Acad Sci USA 98:14108–14113

    Google Scholar 

  24. Neuhaus J (1990) Orthogonal arrays of particles in astroglial cells: quantitative analysis of their density, size, and correlation with intramembranous particles. Glia 3:241–251

    Google Scholar 

  25. Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P (2001) Kir4.1 potassium channel subunit is crucial for oligodendrocyte development in vivo myelination. J Neurosci 21:5429–5438

    Google Scholar 

  26. Neusch C, Weishaupt JH, Bähr M (2003) Kir channels in the CNS: emerging new roles and implications for neurological diseases. Cell Tissue Res 311:131–138

    Google Scholar 

  27. Newman E, Reichenbach A (1996) The Müller cell: a functional element of the retina. Trends Neurosci 19:307–312

    Article  Google Scholar 

  28. Nico B, Frigeri A, Nicchia GP, Quondamatteo F, Herken R, Errede M, Ribatti D, Svelto M, Roncali L (2001) Role of aquaporin-4 water channel in the development and integrity of the blood-brain barrier. J Cell Sci 114:1297–1307

    Google Scholar 

  29. 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 17:171–180

    CAS  PubMed  Google Scholar 

  30. Olsen ML, Sontheimer H (2004) Mislocalization of Kir channels in malignant glia. Glia 46:63–73

    Google Scholar 

  31. Orkand RK, Nicholls JG, Kuffler SW (1966) Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J Neurophysiol 29:788–806

    Google Scholar 

  32. Pannicke T, Iandiev I, Uckermann O, Biedermann B, Kutzera F, Wiedemann P, Wolburg H, Reichenbach A, Bringmann A (2004) A potassium channel-linked mechanism of glial cell swelling in the postischemic retina. Mol Cell Neurosci 26:493–502

    Google Scholar 

  33. Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption in excess fluid in vasogenic edema. FASEB J 18:1291–1293

    Google Scholar 

  34. Poopalasundaram S, Knott C, Shamotienko OG, Foran PG, Dolly JO, Ghiani CA, Gallo V, Wilkin GP (2000) Glial heterogeneity in expression of the inwardly rectifying K(+) channel, Kir4.1, in adult rat CNS. Glia 30:362–372

    Google Scholar 

  35. Rascher G, Fischmann A, Kroger S, Duffner F, Grote EH, Wolburg H (2002) Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol 104:85–91

    Google Scholar 

  36. 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 95:11981–11986

    Google Scholar 

  37. Rash JE, Davidson KGV, Yasumura T, Furman CS (2004) Freeze-fracture and immunogold analysis of aquaporin-4 (AQP4) square arrays, with models of AQP4 lattice assembly. Neuroscience 129:915–934

    Google Scholar 

  38. Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA (2002) Aquaporin-4 expression is increased in oedematous human brain tumors. J Neurol Neurosurg Psychiatry 72:262–265

    Google Scholar 

  39. Saadoun S, Papadopoulos MC, Krishna S (2003) Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumors: immunohistochemical case review. J Clin Pathol 56:972–975

    Google Scholar 

  40. Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T (2000) Induction of aquaporin-4 water channel mRNA after focal ischemia in rat. Brain Res Mol Brain Res 78:131–137

    Google Scholar 

  41. Verbavatz J-M, 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 110:2855–2860

    Google Scholar 

  42. Vizuete ML, Venero JL, Vargas C, Ilundain AA, Echevarria M, Machado A, Cano J (1999) Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema. Neurobiol Dis 6:245–258

    Google Scholar 

  43. Warth A, Kröger S, Wolburg H (2004) Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol 107:311–318

    Google Scholar 

  44. Wolburg H (1995) Orthogonal arrays of intramembranous particles: a review with special references to astrocytes. J Hirnforsch 36:239–258

    Google Scholar 

  45. 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 271:4577–4580

    Google Scholar 

Download references

Acknowledgement

We thank Dr. A. Reichenbach (Leipzig) for discussions and careful reading the manuscript.

Author information

Authors and Affiliations

  1. Institute of Pathology, University of Tübingen, Liebermeisterstrasse 8, 72076, Tübingen, Germany

    Arne Warth & Hartwig Wolburg

  2. Institute of Brain Research, University of Tübingen, Tübingen, Germany

    Michel Mittelbronn

Authors
  1. Arne Warth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel Mittelbronn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hartwig Wolburg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hartwig Wolburg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Warth, A., Mittelbronn, M. & Wolburg, H. Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors. Acta Neuropathol 109, 418–426 (2005). https://doi.org/10.1007/s00401-005-0984-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-005-0984-x

Keywords

Search

Navigation