Increased Aquaporin-4 Immunoreactivity in Rat Brain in Response to Systemic Hyponatremia

Vajda, Zsolt; Promeneur, Dominique; Dóczi, Tamás; Sulyok, E.; Frøkiær, Jørgen; Ottersen, Ole Petter; Nielsen, Søren

doi:10.1006/bbrc.2000.2472

Cited by 126 publications

(79 citation statements)

References 36 publications

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“…Previous studies have implicated AQP4 as an important component in the pathogenesis of brain edema (13)(14)(15)(16)(17)(18). Recent studies of mice homozygous for targeted gene disruptions have reported partial protection against acute brain edema; however, these transgenic models are complex, because the mice have global protein deficiencies (19,20).…”

Section: Discussionmentioning

confidence: 99%

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Amiry-Moghaddam

Otsuka

Hurn

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

474

416

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The water channel AQP4 is concentrated in perivascular and subpial membrane domains of brain astrocytes. These membranes form the interface between the neuropil and extracerebral liquid spaces. AQP4 is anchored at these membranes by its carboxyl terminus to ␣-syntrophin, an adapter protein associated with dystrophin. To test functions of the perivascular AQP4 pool, we studied mice homozygous for targeted disruption of the gene encoding ␣-syntrophin (␣-Syn ؊/؊ ). These animals show a marked loss of AQP4 from perivascular and subpial membranes but no decrease in other membrane domains, as judged by quantitative immunogold electron microscopy. In the basal state, perivascular and subpial astroglial end-feet were swollen in brains of ␣-Syn ؊/؊ mice compared to WT mice, suggesting reduced clearance of water generated by brain metabolism. When stressed by transient cerebral ischemia, brain edema was attenuated in ␣-Syn ؊/؊ mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but ␣-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus ␣-syntrophin-dependent anchoring of AQP4 is sensitive to ischemia, and loss of AQP4 from this site may retard the dissipation of postischemic brain edema. These studies identify a specific, syntrophin-dependent AQP4 pool that is expressed at distinct membrane domains and which mediates bidirectional transport of water across the brain-blood interface. The anchoring of AQP4 to ␣-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule. C erebral edema is essentially a loss of water homeostasis entailing a net increase of water flux into the brain. The route of water influx in this life-threatening condition is unknown, and no efficient therapy exists. We have previously shown that the brain expresses a water channel molecule, AQP4, that is strongly enriched in those astrocyte membrane domains forming the interface between brain neuropil and extracerebral spaces filled with blood or cerebrospinal fluid (1-3). To determine whether the pools of AQP4 in these specialized membrane domains are responsible for the fast influx of water that occurs during the development of brain edema, one must specifically eliminate the perivascular and subpial pools of AQP4 while leaving other pools of AQP4 intact. This can be achieved by deletion of ␣-syntrophin (␣-syn), an adapter protein in the dystrophin-associated protein complex that is required for anchoring AQP4 at these specialized membrane domains (4). Mice homozygous for targeted disruption of the gene encoding ␣-syntrophin (␣-Syn Ϫ/Ϫ ) exhibit a marked reduction of AQP4 in perivascular and subpial membranes but not in other locations in brain, because total brain AQP4 protein content is not reduced (4).The first aim of the present study was to use ␣-Syn Ϫ/Ϫ mice to investigate whether a selective depletion of the perivascular AQP4 pool reduces the vol...

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Section: Discussionmentioning

confidence: 99%

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Amiry-Moghaddam

Otsuka

Hurn

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

474

416

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“…It was shown previously that AQP4-ir increased in the rat brain after systemic hyponatremia (Vajda et al, 2000). Because there was no increase in protein levels in Western blots, the authors proposed that the phosphorylation of AQP4 facilitated the detection of the protein in the cell membrane by immunohistochemistry (Vajda et al, 2000). Several putative PKA, PKC, CKII, and CaMKII phosphorylation sites have been described which could allow a rapid regulation of AQP4 (Gunnarson et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Early Aquaporin 4 Induction against Postischemic Edema Formation

Hirt

Ternon

Price

et al. 2008

J Cereb Blood Flow Metab

125

116

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Aquaporin 4 (AQP4) is a water channel involved in water movements across the cell membrane and is spatially organized on the cell surface in orthogonal array particles (OAPs). Its role in edema formation or resolution after stroke onset has been studied mainly at late time points. We have shown recently that its expression is rapidly induced after ischemia coinciding in time with an early swelling of the ischemic hemisphere. There are two isoforms of AQP4: AQP4-M1 and AQP4-M23. The ratio of these isoforms influences the size of the OAPs but the functional impact is not known. The role of the early induction of AQP4 is not yet known. Thrombin preconditioning in mice provides a useful model to study endogenous protective mechanisms. Using this model, we provide evidence for the first time that the early induction of AQP4 may contribute to limit the formation of edema and that the AQP4-M1 isoform is predominantly induced in the ischemic tissue at this time point. Although it prevents edema formation, the early induction of the AQP4 expression does not prevent the blood-brain barrier disruption, suggesting an effect limited to the prevention of edema formation possibly by removing of water from the tissue.

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“…AQP4 up-regulation has also been found in the brain of a human patient with brain edema secondary to acute bacterial meningitis (29), suggesting that similar mechanisms might occur in humans. Increased astrocyte AQP4 expression is not restricted to meningitis, but occurs in several pathologies associated with cytotoxic brain edema, including traumatic brain injury in humans (29) and rats (30), cerebral ischemia in humans (31) and rats (32), and hyponatremia in rats (33). Direct measurement of BBB water permeability (P f S), as was done here for meningitis, will be required to determine whether AQP4 up-regulation also accelerates brain water accumulation in these conditions.…”

Section: Discussionmentioning

confidence: 99%

Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis

Papadopoulos

Verkman

2005

Journal of Biological Chemistry

276

193

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The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitisinduced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 ؎ 1 versus 25 ؎ 5 cm H 2 O) and brain water accumulation (2 ؎ 1 versus 9 ؎ 1 l) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a ϳ5-fold higher water permeability (P f ) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured P f and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 upregulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.Streptococcus pneumoniae (pneumococcus) is the most common and aggressive meningeal pathogen (1-3). The overall incidence of pneumococcal meningitis is rising (4, 5) and the emergence of penicillin-resistant S. pneumoniae makes treatment harder (6, 7). Even with effective antibiotic treatment, mortality from pneumococcal meningitis is 10 -30%, with 30 -50% of patients acquiring permanent neurological deficits (1-3). A major complication associated with unfavorable outcome in bacterial meningitis is brain edema, which causes a rise in intracranial pressure potentially leading to brain ischemia, herniation, and death (8, 9). The molecular mechanisms responsible for the formation and absorption of excess fluid in brain edema associated with meningitis are poorly understood.The two main types of brain edema are cytotoxic and vasogenic (10). Cytotoxic edema, as occurs in ischemic stroke, refers to cell swelling that primarily affects astroglial cells. Vasogenic edema, as occurs in brain tumors, involves accumulation of excess fluid in the extracellular space of the brain parenchyma because of a leaky blood-brain barrier (BBB). 1 Although both types of brain edema are thought to co-exist in meningitis (8, 9), their relative contributions to brain swelling are not known.Recently, the bidirectional water channel aquaporin-4 (AQP4) has been found to play an important role in brain-water homeostasis (11-16). AQP4 protein is expressed strongly in astroglia at the BBB and CSF-brain interfaces (17, 18), suggesting involvement in water movement between fluid compartments (blood and CSF) and brain parenchyma. AQP4 deletion markedly reduced brain swelling in mouse models of cytotoxic brain edema, includin...

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Increased Aquaporin-4 Immunoreactivity in Rat Brain in Response to Systemic Hyponatremia

Cited by 126 publications

References 36 publications

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Protective Role of Early Aquaporin 4 Induction against Postischemic Edema Formation

Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis

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