Abstract
Water serves as the primary substance in all living cells and is an essential molecule involved in numerous biological processes critical for maintaining homeostasis in the central nervous system (CNS). Disruptions in water balance can occur in conditions such as cerebral edema, where fluid accumulation results in increased intracranial pressure (ICP). Aquaporins (AQPs) are transmembrane proteins that play a vital role in the rapid transport of water across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, and AQP11) have been identified in brain tissue. This review summarizes the latest advancements in our understanding of the critical role of AQPs in regulating water transport in brain edema. Abundant evidence indicates that AQP4, the most prevalent AQP in the CNS, regulates brain water transport and contributes to both cytotoxic and vasogenic edema, suggesting that AQP4 may serve as a potential therapeutic target for brain edema. Additionally, some studies have indicated that AQP1 plays a significant role in the formation of cerebrospinal fluid (CSF) and the maintenance of steady-state ICP. However, to date, these findings have not been translated into clinical practice. There is an urgent need to develop specific AQP inhibitors and activators to explore the potential benefits of modulating the functions of AQP1 and AQP4 in the context of brain edema.
1 Introduction
Water is the most abundant component of all living cells and organisms, and the effective regulation of water balance is crucial for numerous biochemical processes. Approximately 80% of the brain is composed of water, which circulates among various compartments, including blood, cerebrospinal fluid (CSF), and the intracellular and interstitial spaces of brain parenchyma. It traverses the blood-brain and the blood-CSF interfaces. Disturbances in water homeostasis can have severe detrimental effects on brain function and significantly contribute to the pathophysiology of traumatic brain injury (TBI), stroke, and various cerebral disorders (Fishman, 1975).
Cerebral edema is defined as the excessive accumulation of water within the brain parenchyma, which is associated with various cerebral injuries, including ischemic injury, TBI, and brain tumors. This condition ultimately leads to an increase in intracranial pressure (ICP) (Chen et al., 2024). Elevated ICP can further impair the regulation of cerebral blood flow (CBF), eventually resulting in additional brain injury and potentially death. The regulation of brain water balance is of clinically significant. However, the exact mechanisms involved in water accumulation and clearance in the brain remain unclear. Currently, the treatment of cerebral edema mainly focuses on removing excess water from the brain parenchyma and reducing ICP, which helps to limit the damage but fails to address the underlying causes of brain edema. Therefore, the development of novel therapeutic drugs that directly target the molecular key players in the mechanisms of edema formation will contribute to adjusting current therapies and establishing new treatment strategies.
Aquaporins (AQPs) are a recently identified family of transmembrane water channel proteins that facilitate water transport and play a significant role in regulating water homeostasis across various tissues, including the nervous system (Zhou et al., 2022). Numerous recent studies have shown that AQP water channels are crucial for maintaining brain water balance and for the development and resolution of edema. This review specifically examines the role of AQPs in brain water transport and cerebral edema.
2 Aquaporins
2.1 Family members
To date, a total of 13 isoforms (AQP0–12) (Figure 1) are included in the AQP superfamily across numerous mammalian tissues, such as the kidney, nervous system, lung, liver, gastrointestinal tract, eye, heart, skin, and adipose tissue (Czyżewski et al., 2024). AQP monomers weigh approximately 28 kDa and typically encompass six highly hydrophobic transmembrane spanning domains and a central water pore (Eriksson et al., 2013) (Figure 2). These proteins are currently classified into three principal subfamilies based on their pore selectivity and sequence homology (da Silva et al., 2022): (a) conventional water-selective AQPs or aquaporins (AQP0,−1,−2,−4,−5,−6, and−8) are primarily permeable to water at a high flow rate. Nevertheless, AQP1, AQP6, and AQP8 also transport volatile solutes such as CO2, anions, and ammonia, respectively (Galli et al., 2021); (b) aquaglyceroporins (AQP3,−7,−9, and−10) are permeable to glycerol, urea, and other small solutes in addition to water; and (c) superaquaporins or subcellular aquaporins (AQP11 and 12) are localized within the cytosol and are involved in intracellular homeostasis. Additionally, a fourth subgroup was reported relatively recently, which included paralogs belonging to the aforementioned three subgroups (AQP0, 1, 3, 5, 8, 9, and 11), named peroxiporins. These AQPs have high permeability to hydrogen peroxide (H2O2) and play a significant role in eliminating excessive reactive oxygen species (ROS) (Varadaraj and Kumari, 2020; Montiel et al., 2020; Silva et al., 2022; Krüger et al., 2021; Zhang et al., 2022; Sorrentino et al., 2022). Table 1 summarizes the subdivision of the mammalian AQPs and their basic properties.
Figure 1
Schematic architectures of 13 isoforms (AQP0-12) in the AQP superfamily.
Figure 2
A secondary structure and topology of AQP molecule. AQP monomer has six membranespanning regions (1–6), five loops (A-E) with intracellular amino and carboxy termini as well as internal tandem repeats (top). Each monomer has a water pore (bottom).
Table 1
| Gene symbol | Gene description | Synonym | Subfamily | Tissue expression | Permeability |
|---|---|---|---|---|---|
| AQP0 | Aquaporin 0 | MIP | Classical aquaporins, peroxiporins | Eye lens (Chepelinsky, 2009) | H2O (Gorin et al., 1984), anions (Ehring et al., 1990), H2O2 (Varadaraj and Kumari, 2020) |
| AQP1 | Aquaporin 1 | CHIP28 | Classical aquaporins, peroxiporins | Brain (Qiu et al., 2014), blood vessels (Mints et al., 2007), kidney proximal tubules (Seyahian et al., 2020), lung (Wang et al., 2022), digestive tracts (Liao et al., 2020), eye (Bogner et al., 2016), and ear (Huang et al., 2011) | H2O (Benga et al., 1986), CO2 (Galli et al., 2021), H2O2 (Mints et al., 2007) |
| AQP2 | Aquaporin 2 | NDI2, WCH-CD | Classical aquaporins | Kidney collecting ducts (Takata et al., 2022), trigeminal ganglia (Borsani et al., 2009) | H2O (Fushimi et al., 1993) |
| AQP3 | Aquaporin 3 | GIL | Aquglyceroporins, peroxiporins | Kidney collecting ducts (Lei et al., 2017), skin (Zhang et al., 2021), respiratory (Liu et al., 2007), and digestive tracts (Liao et al., 2020), and brain (Yang et al., 2011) | H2O, urea, glycerol (Ishibashi et al., 1994), NH3 (Litman et al., 2009), arsenite (Sosa et al., 2020), H2O2 (Silva et al., 2022) |
| AQP4 | Aquaporin 4 | MIWC, WCH4 | Classical aquaporins | Brain (Skauli et al., 2022), lung (Wu et al., 2015), eye (Kimball et al., 2021), ear (Hirt et al., 2011), skeletal muscle (Chung et al., 2020), stomach parietal cells (Fukuhara et al., 2014), and kidney collecting ducts (Nielsen et al., 2002) | H2O (Jung et al., 1994), CO2 (Musa-Aziz et al., 2009), NH3 (Assentoft et al., 2016) |
| AQP5 | Aquaporin 5 | PPKB | Classical aquaporins, peroxiporins | Salivary, lacrimal, and sweat glands (Muroi and Isohama, 2021), brain (Yang et al., 2011), ear (Merves et al., 2003) and eye (Bogner et al., 2016) | H2O (Villandre et al., 2022), CO2 (Alishahi and Kamali, 2019), H2O2 (Silva et al., 2022) |
| AQP6 | Aquaporin 6 | KID | Classical aquaporins | Kidney collecting duct cells (Ohshiro et al., 2001) and brain (Nagase et al., 2007) | H2O (Molinas et al., 2017), urea, glycerol (Holm et al., 2004), NH3 (Musa-Aziz et al., 2009), anions (Galli et al., 2021) |
| AQP7 | Aquaporin 7 | GLYCQTL | Aquglyceroporins | Adipocytes (Iena et al., 2022), breast (Dai et al., 2020), testis (Saito et al., 2004), kidney, skeletal muscle (Iena and Lebeck, 2018), and brain (Shin et al., 2006) | H2O, urea, glycerol (Delporte et al., 2009), NH3 (Musa-Aziz et al., 2009), arsenite (Liu et al., 2002) |
| AQP8 | Aquaporin 8 | – | Classical aquaporins, peroxiporins | Pancreas, testis, liver (Ikaga et al., 2015), kidney (Molinas et al., 2012), heart (Yang et al., 2005), and brain (Yang et al., 2011) | H2O, NH3, urea (Kirscht et al., 2018), H2O2 (Krüger et al., 2021) |
| AQP9 | Aquaporin 9 | SSC1 | Aquglyceroporins, peroxiporins | Liver (da Silva et al., 2022), leukocytes (Matsushima et al., 2014), testis (Arena et al., 2011) and brain (Yang et al., 2011) | H2O, urea, glycerol (Sugiyama et al., 2014), NH3 (Litman et al., 2009), arsenite (Liu et al., 2002), lactate (Medina et al., 2021), H2O2 (Zhang et al., 2022) |
| AQP10 | Aquaporin 10 | AQPA-HUMAN | Aquglyceroporins | Small intestine (Öberg et al., 2011) and testis (Hermo et al., 2004) | H2O, urea, glycerol (Ishibashi et al., 2002) |
| AQP11 | Aquaporin 11 | AQPX1 | Superaquaporins, peroxiporins | Intestine (Zhu et al., 2016), liver, kidney (Ishibashi et al., 2014), testis (Shannonhouse et al., 2014), brain (Trillo-Contreras et al., 2022), heart (Verkerk et al., 2019), and adipose tissue (Frühbeck et al., 2020) | H2O, glycerol, H2O2 (Sorrentino et al., 2022; Frühbeck et al., 2020) |
| AQP12 | Aquaporin 12 | mAQP12 | Superaquaporins | Pancreas (Ohta et al., 2009) | Undetermined |
Summary of mammalian AQPs and their basic properties.
2.2 Presence in the brain
To date, nine subtypes of AQP (AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, and AQP11) have been recognized in various types of brain-resident cells, such as the cerebral cortex, cerebellum, choroid plexus, brain cells, and neural stem cells (as illustrated in Figure 3 and Table 2). However, it is important to note that only AQP1, AQP4, and AQP9 possess significant physiological functions and pathological implications. AQP4 is the most predominant and well-characterized aquaporin identified in the brain, with the brain being the primary site of AQP4 expression in mammals (Jung et al., 1994). In brain tissue, AQP4 is predominantly expressed in glia cells, particularly at the interface between the brain and major water-containing compartments (Rash et al., 1998), indicating its role in the movement of water into and out of the brain. AQP1 is expressed in the ventricular-facing cell plasma membrane of epithelial cells in the choroid plexus, suggesting a role of AQP1 in CSF secretion (Nielsen et al., 1993). AQP9 is the sole aquaglyceroporin expressed in astrocytes of the glia limitans and white matter tracts (Badaut et al., 2004). The function of AQP9 in the brain remains unclear, but its permeability to glycerol suggests that its likely involvement in brain metabolism. Although the transcriptional abundances of AQP1 and AQP9 are extremely low in human and mouse brain cells under physiological conditions, certain upregulations may occur under pathological circumstances (Misawa et al., 2008; Geistlinger et al., 2022).
Figure 3
Brain aquaporin expression. Astrocytes express AQP1, AQP3, AQP4, AQP5, AQP8, and AQP9. Oligodendrocytes express AQP8. Neuron express AQP1, AQP3, AQP5, AQP8, AQP9, and AQP11. Neural stem cells express AQP4, AQP6, AQP8, and AQP9. AQP1, AQP3, AQP5, AQP7, AQP8, and AQP11 are expressed in the choroid plexus. AQP1, AQP3, AQP4, AQP5, AQP6, AQP8, AQP9, and AQP11 are found in the cerebellum. AQP1, AQP3, AQP4, AQP5, AQP8, AQP9, and AQP11 are expressed in the cerebral cortex.
Table 2
| AQP subfamilies | Expressions in brain |
|---|---|
| AQP1 | Cerebral cortex (Park et al., 2021), cerebellum (Wiegman et al., 2008), choroid plexus (Srisook et al., 2022), astrocyte (Sadashima et al., 2020), and neuron (Yu et al., 2020) |
| AQP3 | Cerebral cortex (Yang et al., 2011), cerebellum (Yang et al., 2011), choroid plexus (Mobasheri et al., 2005), astrocyte (Yang et al., 2011), and neuron (Mobasheri et al., 2005) |
| AQP4 | Cerebral cortex (Elsherbini et al., 2022), cerebellum (Zhao et al., 2020), astrocyte (Eide, 2022), and neural stem cells (Kong et al., 2008) |
| AQP5 | Cerebral cortex (Antequera et al., 2022), cerebellum (Yang et al., 2011), choroid plexus (Sveinsdottir et al., 2014), astrocyte (Chai et al., 2013), and neuron (Chai et al., 2013) |
| AQP6 | Cerebellum (Nagase et al., 2007) and neural stem cells (Lee et al., 2010) |
| AQP7 | Choroid plexus (Shin et al., 2006) |
| AQP8 | Cerebral cortex (Yamamoto et al., 2001), cerebellum, choroid plexus (Yang et al., 2011), astrocyte, oligodendrocyte, neuron (Yamamoto et al., 2001) and neural stem cells (La Porta et al., 2006) |
| AQP9 | Cerebral cortex (Liu et al., 2018), cerebellum (Wiegman et al., 2008), astrocyte (Hirt et al., 2018), neuron (Mori et al., 2020) and neural stem cells (Cavazzin et al., 2006) |
| AQP11 | Cerebral cortex, cerebellum (Gorelick et al., 2006), choroid plexus (Koike et al., 2016), and neuron (Gorelick et al., 2006) |
Expressions of AQPs in brain.
Expressions of AQPs are based on detection of either mRNA or protein.
3 Role of AQPs in the brain water homeostasis
In the typical adult brain, water migrates between various compartments (CSF, blood, and both intracellular and interstitial brain parenchyma) in response to differences in hydrostatic and osmotic pressure. Water enters the brain through the blood-brain barrier (BBB) or the choroid plexus and exits through the arachnoid granulations into the venous system (Abbott, 2004). The significant expression of AQP4 at the BBB and in ependymal cells lining the ventricles has promoted initial studies on the crucial role of AQP4 in determining the water permeability of the BBB. AQP4 knockout mice exhibited greater ventricular enlargement and elevated ICP compared to wild-type mice in an experimental model of obstructive hydrocephalus, suggesting a function for AQP4 in CSF absorption (Bloch et al., 2006). Transgenic mice overexpressing AQP4 demonstrated an accelerated progression of brain swelling and poorer outcomes in water intoxication (Yang et al., 2008a). The deletion of AQP1 reduces osmotic water permeability in the choroid plexus by a factor of five. However, CSF production is only reduced by approximately 25% in AQP1 knockout mice compared to wild-type mice, indicating that only a portion of CSF secretion is AQP1-dependent and that there is a substantial contribution from extrachoroidal fluid production by the brain parenchyma (Oshio et al., 2005). Moreover, a study involving AQP1-deficient and AQP4-deficient mice concluded that AQP4, rather than AQP1, aids in mediating water flow into CSF, suggesting that AQP4 plays a vital role in CSF production (Igarashi et al., 2014). These phenotypic studies of AQP4 and AQP1 transgenic mice offer evidence for the roles of these water channels in the physiology of brain water homeostasis under normal and abnormal circumstances.
4 Role of AQPs in the brain edema
Klatzo classified edema into cytotoxic and vasogenic types (Klatzo, 1967). Fishman later added another type, termed interstitial (or hydrocephalic) edema, observed in patients with hydrocephalus (Fishman, 1975). Cytotoxic edema represents the intracellular accumulation of water reliant on ionic imbalances and affects glial, neuronal, and endothelial cells within the brain. The typical cytotoxic edema occurs in the early stages of ischemia or hypoxia, cerebral malaria, and hyponatremia, when brain cells are impaired but the BBB remains intact. In contrast, vasogenic edema emerges due to the disruption of the BBB, leading to an enhanced permeability of capillary endothelial cells to albumin and other plasma proteins (Hu et al., 2023). Nevertheless, in most instances, these two types of edema coexist, and one type of edema gradually transforms into the other (Pasantes-Morales and Cruz-Rangel, 2010). Interstitial cerebral edema refers to the outflow of CSF from the ventricles into the interstitial space of the brain. Patients with hydrocephalus or meningitis are affected by this etiology. The elevated pressure on the brain and CSF forces fluid into the brain parenchyma. The accumulation of fluid in the extracellular space, primarily in the white matter, leads to cerebral edema.
4.1 AQPs and cytotoxic edema
Since astrocytes are the major cell type that swells in cytotoxic brain edema (Kimelberg, 1995) and are the predominant sites of AQP4 expression in the brain (González-Marrero et al., 2022), it can be logically inferred that AQP4 plays a crucial role in the development of cytotoxic brain edema (Figure 4). Manley et al. (2000) demonstrated that AQP4-deficient mice performed better than their wild-type counterparts in cytotoxic brain edema, employing two models of cytotoxic edema, namely acute water intoxication and early cerebral ischemia. Additionally, Papadopoulos and Verkman (2005) reported that AQP4-deficient mice had significantly less brain water accumulation in meningitis-induced brain edema, another cytotoxic edema model. Recently, Sucha et al. (2022) discovered that simultaneous deletion of AQP4 and Transient Receptor Potential Vanilloid 4 mitigated the cytotoxic edema following ischemic injury. AQP4 molecules are linked to the cell membrane by α-syntrophin, dystrophin, and other proteins, which are crucial for the localization of AQP4 to the astrocytic end-feet. Comparable studies have validated the role of AQP4 in cytotoxic edema using the dystrophin null mdx-βgeo transgenic mice and the α-syntrophin null mice, which are considered as alternative models for the AQP4-null genotype (Moëlo et al., 2023; Vajda et al., 2002). Furthermore, AQP5 is also implicated in cytotoxic brain edema. Yamamoto et al. (2001) indicated that hypoxia elicited a significant decrease in AQP5 mRNA in rat astrocytes, suggesting that AQP5 might be one of the candidates for inducing cytotoxic edema in the central nervous system after ischemic injury.
Figure 4
Role of AQP4 in cytotoxic edema. The swelling of the endfeet of astrocytes after water enters through the AQP4 water channel is a characteristic of cytotoxic edema.
4.2 AQPs and vasogenic edema
AQP4 may not only facilitate water entry into the brain but also its exit (Figure 5). Overexpression of AQP4 has been observed in meningiomas, which is associated with the response to vasogenic edema of meningiomas (Faropoulos et al., 2021). In relation to vasogenic edema, Papadopoulos et al. (2004) noted that AQP4 deletion had the opposite effect (increased brain swelling) in three vasogenic edema models: intraparenchymal fluid infusion, focal cortical freeze injury, and brain tumor cell implantation. Following continuous intracerebral fluid infusion, AQP4-deficient mice exhibited higher ICP and brain water content compared to wild-type controls. Cortical freeze injury gives rise to a significantly greater brain water content and higher ICP in AQP4-deficient mice. In a brain tumor edema model involving stereotactic implantation of melanoma cells, AQP4-deficient mice showed higher ICP and accelerated neurological deterioration (Papadopoulos et al., 2004). A similar outcome was observed with the injection of Staphylococcus aureus to generate brain abscesses in the striatum of mice. AQP4-deficient mice exhibited more than twice the increase in brain water content, along with significantly higher ICP than wild-type control mice (Bloch et al., 2005). These findings suggest that AQP4 activators might alleviate vasogenic brain edema in humans. Additionally, AQP5 also plays a role in water homeostasis in vasogenic brain edema. Lambertz et al. (2013) demonstrated that the occurrence and severity of peritumoral edema in meningiomas were associated with AQP5 polymorphism A(-1364)C.
Figure 5
Different role of AQP4 in cytotoxic and vasogenic edema. In cytotoxic edema the water accumulation in astrocyte is AQP4 dependent. Contrary to cytotoxic edema, AQP4 plays a favorable role in water elimination in vasogenic edema.
4.3 AQPs and interstitial (or hydrocephalic) edema
Given the crucial roles of AQP1 in CSF production and AQP4 in CSF absorption, it is proposed that they are involved in hydrocephalic brain edema resulting from the increase in CSF pressure and disruption of the BBB. The increased expression of AQP1 highlights the importance of excessive CSF production and an intact blood-CSF barrier during the development of hydrocephalic edema (Kim and Jung, 2011). Experiments have demonstrated that AQP1-null mice exhibit a fivefold reduction in osmotic water permeability in the choroid plexus compared to wild-type mice, indicating that reducing the function of AQP1 decreases the occurrence of non-obstructive hydrocephalus (Oshio et al., 2003). Several studies have reported elevated expression of AQP4 in connection with hydrocephalus, including congenital hydrocephalus in Texas rats (Paul et al., 2011), idiopathic communicating internal hydrocephalus in dogs (Schmidt et al., 2016), and inflammatory communicating hydrocephalus in rats (Tourdias et al., 2009). In patients with congenital hydrocephalus, the expression of AQP4 is elevated in both CSF and brain parenchyma (Castañeyra-Ruiz et al., 2013). In a model of obstructive hydrocephalus induced by kaolin injection, AQP4-deficient mice exhibited significant ventriculomegaly and increased ICP, which was suggested to result from impaired transependymal water clearance (Bloch et al., 2006). These discoveries suggest a compensatory function of AQPs in the water dynamics of hydrocephalic edema.
4.4 Regulation of AQPs expression in the brain edema
4.4.1 Vasopressin
Vasopressin (VP) plays a crucial role in the development of brain injury and has been shown to regulate AQP4 expression in cases of brain edema. Studies indicate that astrocyte AQP4 levels were reduced by vasopressin 1a receptor (V1AR) antagonist treatment in a model of TBI, concurrently with the prevention of cell swelling and a reduction in edema (Marmarou et al., 2014; Taya et al., 2008). Additionally, V1AR has been found to upregulated cerebreal AQP1 expression, suggesting that V1AR may worsen brain edema formation post-TBI (Rauen et al., 2020). There is a substantial evidence suggesting that V1AR antagonists help reduce the development of cytotoxic brain edema by decreasing the upregulation of AQP4 (Kleindienst et al., 2013). In a stroke model induced by middle cerebral artery occlusion followed by reperfusion, it was observed that administering a V1AR antagonist decreased AQP4 expression in cytotoxic brain edema (Okuno et al., 2008).
4.4.2 Dopamine
Dopamine has been demonstrated to curtail the proliferation of striatal astrocytes in vitro and downregulate AQP4 expression in primary cultured astrocytes (Küppers et al., 2008). It has been reported that AQP4 expression is augmented in the substantia nigra following tissue-type plasminogen activator-induced degeneration of dopaminergic neurons (Villarán et al., 2009). Collectively, these studies imply that dopamine might exert a persistent suppressive effect on AQP4 expression. In a model of TBI, it has been reported that dopamine deteriorates cerebral edema formation shortly after impact (Beaumont et al., 2000). This effect has been attributed to the vasopressor action of dopamine, which facilitated vasogenic edema.
4.4.3 Erythropoietin
In recent years, a potent neuroprotective agent, erythropoietin (EPO), has been demonstrated to enhance the permeability of astrocyte AQP4 and might directly lower the risk of astrocyte swelling in stroke and other brain disorders (Gunnarson et al., 2009). In an animal hydrocephalus model, EPO treatment significantly mitigated the dilation of the cerebral ventricles in obstructive hydrocephalus by augmenting the expression of AQP4 (Rizwan Siddiqui et al., 2018). The administration of EPO post-TBI inhibited the reduction of AQP4, alleviated early cytotoxic brain edema, and maintained the structural and functional characteristics of the BBB, thereby weakening the vasogenic edema response (Blixt et al., 2018).
4.4.4 Thyroid transcription factor-1
Thyroid transcription factor-1 (TTF-1), a transcriptional regulator containing a homeodomain and is coexpressed with AQP1 in the rat brain choroid plexus, has been reported to enhance the transcription of the AQP1 gene (Kim et al., 2007). Consequently, inhibiting the synthesis of TTF-1 increased the survival rate of animals with acute water intoxication-induced brain edema by suppressing AQP1 expression.
4.5 Interactions between AQP4 and other trans-membrane structures
4.5.1 AQP4 and Kir4.1
Astrocytes-mediated potassium (K+) homeostasis is critically important for regulating neuronal excitability. An early study revealed that AQP4 is co-localized with the inward rectifier potassium channel Kir4.1 in the end-feet of retinal Müller cells, suggesting a functional interaction between the two (Nagelhus et al., 1999). The uncoupled expression of AQP4 and Kir4.1 on astrocytic end-feet contributes to the development of cytotoxic edema in the brain following subarachnoid hemorrhage (Yan et al., 2012).
4.5.2 AQP4 and calcium signal transduction
Calcium (Ca2+) signaling mediates of bidirectional interactions between neurons and astrocytes. Impaired Ca2+ signaling plays a critical role in the progression of brain edema. Recent evidence suggests that AQP4 is involved in Ca2+ signaling in astrocytes. The deletion of AQP4 reduces Ca2+ signaling induced by hypo-osmotic stress in these cells (Thrane et al., 2011). This finding indicates that Ca2+ signals may result from AQP4-induced astrocyte swelling rather than being directly induced by AQP4 itself. Edema leads to astrocyte swelling, and the presence of AQP4 exacerbates this condition.
4.5.3 AQP4 and Connexin 43
Connexin 43 (Cx43) is a prominent gap junction protein that is extensively expressed in the end-feet of astrocytes. It mediates intracellular interactions by facilitating the transport of ionic and molecules. Recent studies have linked Cx43 to abnormal neuro-differentiation associated with brain injury (Samarasinghe et al., 2014). Both Cx43 and AQP4 play crucial roles in the development of brain edema, with Cx43 potentially acting as a downstream effector of AQP4 (Li et al., 2015). The coordinated action of Cx43 and AQP4, along with K+ channels (Kir4.1/Kir5.1), ensures the efficient clearance of K+ from astrocytes into the vascular system (Lichter-Konecki et al., 2008).
4.6 AQPs and the glymphatic system in the brain edema
The glymphatic system (GS) is a recently discovered microscopic fluid clearance system composed of astrocytic perivascular tunnels that eliminate metabolic wastes from the brain. In this system, the CSF and interstitial fluid (ISF) continuously exchange. It comprises three key compartments: a periarterial CSF influx pathway, a perivenous ISF efflux pathway, and a parenchymal exchange pathway that relies on astrocytic AQP4 (Iliff et al., 2012). Since this discovery, increasing evidence indicates that the GS dysfunction is associated with the formation of brain edema, as it involves AQP4, which plays a crucial role in regulating water homeostasis. The water flow through AQP4 is bidirectional. AQP4 might potentially contribute to astrocytic swelling and cytotoxic edema by facilitating water influx into astrocytes during the early stages of ischemic stroke. However, in the later stages of ischemic stroke, when vasogenic edema becomes the primary cause of brain swelling due to the BBB breakdown, AQP4 could serve the purpose of alleviating brain edema by mediating the transport of excess water from the interstitial space to the GS. By promoting the AQP4 polarization to improve the GS function, it might facilitate the inflow of edema fluids, but it can also significantly enhance downstream drainage function, thereby reducing brain edema (Zhu et al., 2024).
5 Anti-edema drug: AQPs as targets
The management of brain edema involves sedation and the prevention of hypercapnia to avoid elevated intracranial pressure. This includes the administration of intravenous hyperosmolar solutions, such as mannitol and hypertonic saline. Corticosteroids are utilized for treating brain tumors. Surgical resection of the underlying lesion may be performed, and in severe cases, decompressive craniectomy is indicated. For critically ill patients, invasive monitoring of intracranial pressure and cerebral perfusion pressure is conducted to optimize treatment. However, many of these therapies for reducing brain swelling were introduced in the early to mid-20th century, and their efficacy remains limited.
Water transport is a crucial process that contributes to human cerebral edema. Consequently, the utilization of AQP-targeted drugs to regulate water transport would offer novel prospects for therapeutic approaches to brain edema. Nevertheless, at present, there are currently a limited number of AQP-specific pharmacological modulators. Despite being non-specific, certain drugs that enhance or suppress AQP4 activity provide effective therapy in both the formation and resolution of edema. Bumetanide has been demonstrated to prevent edema formation following brain ischemia by reducing AQP4 expression (Migliati et al., 2010; Chen et al., 2023). However, bumetanide is a loop diuretic that inhibits the Na+/K+/2Cl− cotransporter isoform (Boyarko et al., 2023), and its benefits on cerebral edema might also be attributed to the aberration of Na+/K+/2Cl− cotransporter 1 expression in endothelial cells (Yang et al., 2019; O'Donnell et al., 2004). Therefore, it is challenging to comprehend the specific impact of AQP4 on edema formation. Acetazolamide (AZA), one of the most prevalently used drugs for lowering ICP and reducing CSF secretion, was also regarded as an inhibitor of AQP1 and AQP4 (Uldall et al., 2017; Gao et al., 2006). However, contrary to the aforementioned results, Yang et al. (2008b) found no significant inhibition of AQP4 water permeability by AZA. Similarly, methazolamide (MZA), another sulfonamide carbonic anhydrase inhibitor, also exhibited no significant effect on water permeability (Tanimura et al., 2009). Instead of a specific pharmacological drug to suppress AQP4, small interfering RNA (siRNA) technology has been employed to silence AQP4 in primary cultured astrocytes to prevent glutamate-induced astrocyte swelling (Lu et al., 2022). AQP4-siRNA was used to mitigate TBI induced edema by modifying post-traumatic AQP4 polarity reversal in rats (Lu et al., 2020). Similar findings have been documented by Guan et al. (2020), Chen et al. (2016), Fukuda et al. (2013), and others. While the siRNA approach is unlikely to be utilized as a specific drug for preventing edema formation, research on AQP4 inhibition by siRNA in animals will be valuable for validating the hypothesis that inhibiting AQP4 activity is a potential therapeutic target for managing brain edema.
6 Summary and future perspectives
In this review, data from cellular and in vivo animal studies strongly support the idea that AQPs play a functional role in brain water transport. The modulation of water transport is an integral component of controlling edema. Increasing evidence indicates that AQP4 has been shown to influence the accumulation and elimination of edema fluid. The careful modulation of AQP4 in different types of edema is particularly significant because AQP4 has dual roles in brain edema. In the early cytotoxic edema phase, AQP4 promotes the formation of edema fluid. In vasogenic brain edema, AQP4 enhances the rate of edema fluid elimination. Therefore, AQP4 inhibitors would be necessary to protect the brain in cytotoxic edema, while AQP4 activators are anticipated to facilitate the elimination of vasogenic brain edema. Unfortunately, as of now, no effective drugs for altering AQP4 expression or function have been identified. Additionally, AQP4 is expressed in many human tissues involved in crucial cellular and organ functions, such as urinary concentration, exocrine glandular secretion, and metabolism. Therefore, AQP4-selective therapeutic is required, which is a challenge since there are conserved amino acid sequences in the pore regions of various AQP subtypes. Furthermore, there are other brain-AQPs (AQP1 and 9) whose expression changes in brain disorders, but little is known about their pathophysiological effects. It is not clear whether there is an interaction between the different subtypes during edema and whether the other AQPs present in the brain also play roles in brain edema.
Statements
Author contributions
YL: Conceptualization, Writing – original draft, Writing – review & editing. YW: Investigation, Visualization, Writing – original draft. XH: Investigation, Writing – original draft. HZ: Investigation, Writing – original draft. YG: Conceptualization, Writing – review & editing. XZ: Conceptualization, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key R&D Program of China 2020YFC2005000, the National Natural Science Foundation of China Grants 81970606 (to XZ), 81970595 (to YG), and the General Project of the Department of Education of Liaoning Province JYTMS20230566 (to YL). This work was also supported by the Youth Talent Cultivation Fund Project of Dalian Medical University (to YL).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Gen AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CSF, cerebrospinal fluid; TBI, traumatic brain injury; ICP, intracranial pressure; CFB, cerebral blood flow; AQPs, Aquaporins; ROS, reactive oxygen species; BBB, blood-brain barrier; VP, vasopressin; V1AR, vasopressin 1a receptor; EPO, erythropoietin; TTF-1, thyroid transcription factor-1; GS, glymphatic system; ISF, interstitial fluid; AZA, acetazolamide; MZA, methazolammide; siRNA, small interfering RNA.
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Summary
Keywords
aquaporins, water channels, water transport, brain edema, cytotoxic, vasogenic, hydrocephalus
Citation
Li Y, Wang Y, Huang X, Zhang H, Guan Y and Zhang X (2025) Role of aquaporins in brain water transport and edema. Front. Neurosci. 19:1518967. doi: 10.3389/fnins.2025.1518967
Received
29 October 2024
Accepted
13 January 2025
Published
29 January 2025
Volume
19 - 2025
Edited by
Paola Bagnoli, University of Pisa, Italy
Reviewed by
Marco Mainardi, University of Padua, Italy
Liu Hui, Chongqing Medical University, China
Updates
Copyright
© 2025 Li, Wang, Huang, Zhang, Guan and Zhang.
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*Correspondence: Youfei Guan guanyf@dmu.edu.cnXiaoyan Zhang xyzhang@hsc.ecnu.edu.cn
†These authors have contributed equally to this work
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