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The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Bottom Line: 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.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- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus

Schematic summary of a beneficial role AQP4 upregulation plays during the edema resolution phase. The upregulation of AQP4 causes increased water clearance from the tissue, which in turn causes decreased BBB disruption because of decreased pressure, and there is less neutrophil infiltration and decreased pro inflammatory cytokines. This causes decreased MMP production (Candelario-Jalil et al., 2009) which possibly results in less destruction of the basal lamina and tight junctions and causes an even greater decrease of the BBB. In another pathway (dotted lines), the increased water clearance from the tissue and extracellular space causes changes in the osmotic pressure, changing the activation state of the stretch activated ion channels expressed in microglia (Lewis et al., 1993; Eder et al., 1998; Schlichter et al., 2011), causing less microglial activation, leading to decreased pro-inflammatory cytokine release. The resulting decrease in BBB disruption/permeability leads to decreased vasogenic edema or better edema resolution. Finally, this scheme outlines the potential link between AQP4, edema and neuroinflammation. Reproduced with permission from Fukuda and Badaut (2012).
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Figure 5: Schematic summary of a beneficial role AQP4 upregulation plays during the edema resolution phase. The upregulation of AQP4 causes increased water clearance from the tissue, which in turn causes decreased BBB disruption because of decreased pressure, and there is less neutrophil infiltration and decreased pro inflammatory cytokines. This causes decreased MMP production (Candelario-Jalil et al., 2009) which possibly results in less destruction of the basal lamina and tight junctions and causes an even greater decrease of the BBB. In another pathway (dotted lines), the increased water clearance from the tissue and extracellular space causes changes in the osmotic pressure, changing the activation state of the stretch activated ion channels expressed in microglia (Lewis et al., 1993; Eder et al., 1998; Schlichter et al., 2011), causing less microglial activation, leading to decreased pro-inflammatory cytokine release. The resulting decrease in BBB disruption/permeability leads to decreased vasogenic edema or better edema resolution. Finally, this scheme outlines the potential link between AQP4, edema and neuroinflammation. Reproduced with permission from Fukuda and Badaut (2012).

Mentions: A central role of AQP4 in neuroinflammation is in the established astrocyte proliferative response in ischemia (Kuppers et al., 2008). AQP4 was also detected on reactive microglia following LPS injection in rats, but the significance of this expression is poorly understood (Tomás-Camardiel et al., 2004). AQP4 is also upregulated in vasogenic edema, where it occurs as a result of BBB disruption. This suggests associations between AQP4-regulated water flux and neuroinflammation (Fukuda and Badaut, 2012). Pro-inflammatory mediators including toxic cytokines IL-1 and TNF-α released by both activated microglia and by neutrophils, have been found to release matrix metalloproteinases (MMPs) in in vitro astrocyte cultures (Candelario-Jalil et al., 2009; Xia et al., 2010). MMPs are primary components of the neuroinflammatory response being partially responsible for BBB disruption (Rosell et al., 2006). MMP-9 degrades agrin while MMP-3 degrades dystroglycan (Wolburg-Buchholz et al., 2009), both of which play a pivotal role in OAP formation and AQP4 assembly in astroglial end-foot membranes (Noel et al., 2009; Fallier-Becker et al., 2011). The neuroinflammation produced by ischemia leads to upregulation of MMPs which cause AQP4-OAP disruption, and possibly exacerbate BBB disturbance and worsen the edema (Rosell et al., 2006). Development of vasogenic edema also amplifies BBB disruption due to increased hydrostatic pressure. AQP4 may also have a role in neuroinflammation via edema resolution (Figure 5). Up-regulation of perivascular AQP4 causes enhanced resorption of extracellular edema fluid which eases hydrostatic pressure and BBB disruption. As a result there is less neutrophil infiltration, less pro-inflammatory cytokine production and less MMP activation (Fukuda and Badaut, 2012). Stretch-activated Cl− channels expressed on microglia are activated to a lesser extent because of pressure differences due to resorption of edema fluid. This leads to less activated microglia and a decrease in pro-inflammatory cytokine release (Eder et al., 1998; Fukuda and Badaut, 2012).


The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Schematic summary of a beneficial role AQP4 upregulation plays during the edema resolution phase. The upregulation of AQP4 causes increased water clearance from the tissue, which in turn causes decreased BBB disruption because of decreased pressure, and there is less neutrophil infiltration and decreased pro inflammatory cytokines. This causes decreased MMP production (Candelario-Jalil et al., 2009) which possibly results in less destruction of the basal lamina and tight junctions and causes an even greater decrease of the BBB. In another pathway (dotted lines), the increased water clearance from the tissue and extracellular space causes changes in the osmotic pressure, changing the activation state of the stretch activated ion channels expressed in microglia (Lewis et al., 1993; Eder et al., 1998; Schlichter et al., 2011), causing less microglial activation, leading to decreased pro-inflammatory cytokine release. The resulting decrease in BBB disruption/permeability leads to decreased vasogenic edema or better edema resolution. Finally, this scheme outlines the potential link between AQP4, edema and neuroinflammation. Reproduced with permission from Fukuda and Badaut (2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389728&req=5

Figure 5: Schematic summary of a beneficial role AQP4 upregulation plays during the edema resolution phase. The upregulation of AQP4 causes increased water clearance from the tissue, which in turn causes decreased BBB disruption because of decreased pressure, and there is less neutrophil infiltration and decreased pro inflammatory cytokines. This causes decreased MMP production (Candelario-Jalil et al., 2009) which possibly results in less destruction of the basal lamina and tight junctions and causes an even greater decrease of the BBB. In another pathway (dotted lines), the increased water clearance from the tissue and extracellular space causes changes in the osmotic pressure, changing the activation state of the stretch activated ion channels expressed in microglia (Lewis et al., 1993; Eder et al., 1998; Schlichter et al., 2011), causing less microglial activation, leading to decreased pro-inflammatory cytokine release. The resulting decrease in BBB disruption/permeability leads to decreased vasogenic edema or better edema resolution. Finally, this scheme outlines the potential link between AQP4, edema and neuroinflammation. Reproduced with permission from Fukuda and Badaut (2012).
Mentions: A central role of AQP4 in neuroinflammation is in the established astrocyte proliferative response in ischemia (Kuppers et al., 2008). AQP4 was also detected on reactive microglia following LPS injection in rats, but the significance of this expression is poorly understood (Tomás-Camardiel et al., 2004). AQP4 is also upregulated in vasogenic edema, where it occurs as a result of BBB disruption. This suggests associations between AQP4-regulated water flux and neuroinflammation (Fukuda and Badaut, 2012). Pro-inflammatory mediators including toxic cytokines IL-1 and TNF-α released by both activated microglia and by neutrophils, have been found to release matrix metalloproteinases (MMPs) in in vitro astrocyte cultures (Candelario-Jalil et al., 2009; Xia et al., 2010). MMPs are primary components of the neuroinflammatory response being partially responsible for BBB disruption (Rosell et al., 2006). MMP-9 degrades agrin while MMP-3 degrades dystroglycan (Wolburg-Buchholz et al., 2009), both of which play a pivotal role in OAP formation and AQP4 assembly in astroglial end-foot membranes (Noel et al., 2009; Fallier-Becker et al., 2011). The neuroinflammation produced by ischemia leads to upregulation of MMPs which cause AQP4-OAP disruption, and possibly exacerbate BBB disturbance and worsen the edema (Rosell et al., 2006). Development of vasogenic edema also amplifies BBB disruption due to increased hydrostatic pressure. AQP4 may also have a role in neuroinflammation via edema resolution (Figure 5). Up-regulation of perivascular AQP4 causes enhanced resorption of extracellular edema fluid which eases hydrostatic pressure and BBB disruption. As a result there is less neutrophil infiltration, less pro-inflammatory cytokine production and less MMP activation (Fukuda and Badaut, 2012). Stretch-activated Cl− channels expressed on microglia are activated to a lesser extent because of pressure differences due to resorption of edema fluid. This leads to less activated microglia and a decrease in pro-inflammatory cytokine release (Eder et al., 1998; Fukuda and Badaut, 2012).

Bottom Line: 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.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- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus