title: Disruption of dystroglycan-laminin interactions modulates water uptake by astrocytes.
abstract: Cerebral edema is a serious complication of ischemic brain injury. Cerebral edema includes accumulation of extracellular fluid due to leakage of the brain's microvessel permeability barrier, and swelling of astrocytes as they absorb water from the extracellular space. Expression of matrix adhesion receptors in brain microvessels decreases in ischemic stroke; this contributes to increased microvessel permeability and detachment of astrocytes from the extracellular matrix (ECM). Since loss of the astrocyte adhesion receptor dystroglycan has been associated with disrupted polarization of ion and water channels, we hypothesized that adhesion of astrocytes to the ECM contributes to regulation of water uptake, and that disruption of matrix adhesion impairs the ability of astrocytes to direct water transport. To test this hypothesis, the capacity of astrocytes to take up water was measured using a fluorescence self-quenching assay under both oxygen/glucose deprivation (OGD) and direct antibody-mediated blockade of α-dystroglycan. Both conditions decreased the rate of water uptake. Moreover, inhibiting proteolytic cleavage of dystroglycan that occurs in OGD abrogated the effect of OGD, but not direct blockade of α-dystroglycan, indicating that interfering with dystroglycan-matrix binding itself affects water uptake. Activation of extracellular signal-related kinase (ERK) by OGD was dependent on α-dystroglycan binding, and inhibition of ERK activity with U0126 abrogated the loss of water uptake following OGD. These studies demonstrate for the first time that water uptake in astrocytes is regulated by dystroglycan-dependent signaling associated with matrix adhesion. This presents a novel potential approach to the treatment of cerebral edema.
authors: Division of Hematology, University of Washington School of Medicine, Harborview Medical Center, PO Box 359756, 325 9th Ave, Seattle, WA 98104, USA. bthawk@uw.edu
authors: Brian T
authors: BT
authors: Hawkins
authors: Yu-Huan
authors: YH
authors: Gu
authors: Yoshikane
authors: Y
authors: Izawa
authors: Gregory J
authors: GJ
authors: Del Zoppo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002070:Butadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D049030:Dystroglycans / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000172:deficiency; D007797:Laminin / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D014867:Water / Q000378:metabolism*
chemical_list: D000906:Antibodies; D002070:Butadienes; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007797:Laminin; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009570:Nitriles; C113580:U 0126; D014867:Water; D049030:Dystroglycans; D005947:Glucose
references: Pharmacol Rev. 2005 Jun;57(2):173-85
references: 15914466
references: Physiology (Bethesda). 2009 Aug;24:257-65
references: 19675357
references: Glia. 2009 Jan 15;57(2):207-21
references: 18720409
references: J Cereb Blood Flow Metab. 2008 Apr;28(4):812-23
references: 18030304
references: Neuroreport. 1999 Nov 26;10(17):3567-72
references: 10619645
references: Cell Commun Signal. 2010 Feb 17;8:3
references: 20163697
references: Glia. 2012 Nov;60(11):1646-59
references: 22782669
references: J Cereb Blood Flow Metab. 2001 Jul;21(7):835-46
references: 11435796
references: Stroke. 2008 Jan;39(1):191-7
references: 18032737
references: Am J Pathol. 2007 Aug;171(2):452-62
references: 17620366
references: J Neurosci Res. 2009 Feb 15;87(3):668-76
references: 18831008
references: Am J Physiol Cell Physiol. 2004 Feb;286(2):C426-32
references: 14576087
references: Matrix Biol. 2010 Mar;29(2):143-51
references: 19800000
references: Stroke. 1997 Apr;28(4):858-65
references: 9099208
references: FASEB J. 2004 Aug;18(11):1291-3
references: 15208268
references: N Engl J Med. 2006 Feb 9;354(6):553-5
references: 16467542
references: Glia. 2004 Aug 1;47(2):138-49
references: 15185393
references: EMBO Rep. 2004 May;5(5):484-9
references: 15071496
references: J Neurotrauma. 2012 Jan 1;29(1):19-31
references: 21988198
references: J Neurosci Res. 2010 Aug 15;88(11):2450-8
references: 20623534
references: Nat Rev Neurosci. 2006 Jan;7(1):41-53
references: 16371949
references: Matrix Biol. 2009 May;28(4):179-87
references: 19303439
references: Dev Neurobiol. 2011 Nov;71(11):1018-39
references: 21780303
references: Nature. 2002 Jul 25;418(6896):422-5
references: 12140559
references: Glia. 2011 Dec;59(12):1822-40
references: 21850672
references: Am J Pathol. 1993 Jul;143(1):154-63
references: 8317546
references: Life Sci. 2011 Jan 3;88(1-2):50-6
references: 21055410
references: Nat Med. 2000 Feb;6(2):159-63
references: 10655103
references: Neuropathology. 2011 Jun;31(3):250-64
references: 21118399
references: PLoS One. 2011 Mar 07;6(3):e17559
references: 21408176
references: Nat Neurosci. 2007 Nov;10(11):1369-76
references: 17965657
references: J Neuropathol Exp Neurol. 2008 May;67(5):417-27
references: 18431255
references: Acta Neuropathol. 2009 Aug;118(2):219-33
references: 19533155
references: J Cereb Blood Flow Metab. 2011 Oct;31(10):1972-85
references: 21772312
references: Ann N Y Acad Sci. 1998 Oct 23;857:256-9
references: 9917851
references: Exp Neurol. 2012 Jan;233(1):283-91
references: 22056225
references: Curr Opin Cell Biol. 1994 Oct;6(5):695-704
references: 7530462
references: Cell. 1994 Jun 3;77(5):675-86
references: 8205617
references: J Cell Sci. 2005 Jun 15;118(Pt 12):2557-66
references: 15928048