Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema

Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2011; 108(2):846-51. DOI: 10.1073/pnas.1015217108
Source: PubMed


Aquaporin-4 (AQP4) is a primary influx route for water during brain edema formation. Here, we provide evidence that brain swelling triggers Ca(2+) signaling in astrocytes and that deletion of the Aqp4 gene markedly interferes with these events. Using in vivo two-photon imaging, we show that hypoosmotic stress (20% reduction in osmolarity) initiates astrocytic Ca(2+) spikes and that deletion of Aqp4 reduces these signals. The Ca(2+) signals are partly dependent on activation of P2 purinergic receptors, which was judged from the effects of appropriate antagonists applied to cortical slices. Supporting the involvement of purinergic signaling, osmotic stress was found to induce ATP release from cultured astrocytes in an AQP4-dependent manner. Our results suggest that AQP4 not only serves as an influx route for water but also is critical for initiating downstream signaling events that may affect and potentially exacerbate the pathological outcome in clinical conditions associated with brain edema.

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    • "et al . , 2011 ) . This result implies that Ca 2+ signals may be evoked by AQP4 - induced astrocyte swelling , rather than by AQP4 directly . Edema induces astrocyte swelling and this is augmented by the presence of AQP4 . Swelling prompts release of toxic neuro - active substances such as glutamate and ATP which mediate aberrant Ca 2+ signaling ( Thrane et al . , 2011 ) . Thus , besides operating as an osmotic flux route , this AQP type may also trigger downstream signaling events and may exacerbate the pathological outcome . Modulation of AQP4 may aid in atten - uating cell swelling and secondary effects such as deleterious ATP release . Activation of purinergic P2X7 receptors by ATP in repair and i"
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    ABSTRACT: Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.
    Frontiers in Cellular Neuroscience 03/2015; 9(34). DOI:10.3389/fncel.2015.00108 · 4.29 Impact Factor
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    • "Acute cortical slices were prepared from P10-20 mice as described previously1617. Briefly, 400 μm acute cortical slices were incubated with rhod-2 (2 mM) for 20 min, before being transferred to a recording chamber where they were imaged and analyzed as outlined before17. ATP (500 μM in aCSF) was injected via a glass microelectrode 40–80 μm into the paravascular space or parenchyma of the slice using a picospritzer (10 psi, 100 ms, Parker Instrumentation). "
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    ABSTRACT: In the brain, a paravascular space exists between vascular cells and astroglial end-foot processes, creating a continuous sheath surrounding blood vessels. Using in vivo two-photon imaging we demonstrate that the paravascular circulation facilitates selective transport of small lipophilic molecules, rapid interstitial fluid movement and widespread glial calcium signaling. Depressurizing the paravascular system leads to unselective lipid diffusion, intracellular lipid accumulation and pathological signaling in astrocytes. As the central nervous system is devoid of lymphatic vessels, the paravascular space may serve as a lymphatic equivalent that represents a separate highway for the transport of lipids and signaling molecules.
    Scientific Reports 09/2013; 3:2582. DOI:10.1038/srep02582 · 5.58 Impact Factor
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    • "In the model proposed here, areolar connective tissue fibroblasts use their cytoskeletal machinery to adjust the tension of the matrix, not simply pull on it. The feedback loop allowing this tension regulation appears to involve osmosensation and ATP signaling, reminiscent of mechanisms used by astrocytes to protect the brain from swelling in the presence of hyponatremia [Risher et al., 2009; Thrane et al., 2011]. In the case of myofibroblasts, continuous stretching over several days may give rise to sustained release of ATP and prolonged and activation of P2Y2 receptors causing an increase alpha-smooth muscle actin (alpha-SMA) production and collagen accumulation [Lu et al., 2012]. "
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    ABSTRACT: The biomechanical behavior of connective tissue in response to stretching is generally attributed to the molecular composition and organization of its extracellular matrix. It also is becoming apparent that fibroblasts play an active role in regulating connective tissue tension. In response to static stretching of the tissue, fibroblasts expand within minutes by actively remodeling their cytoskeleton. This dynamic change in fibroblast shape contributes to the drop in tissue tension that occurs during viscoelastic relaxation. We propose that this response of fibroblasts plays a role in regulating extracellular fluid flow into the tissue, and protects against swelling when the matrix is stretched. This article reviews the evidence supporting possible mechanisms underlying this response including autocrine purinergic signaling. We also discuss fibroblast regulation of connective tissue tension with respect to lymphatic flow, immune function and cancer. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 08/2013; 114(8). DOI:10.1002/jcb.24521 · 3.26 Impact Factor
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