Targeting AQP4 localization as a novel therapeutic target in CNS edema

CNS edema is a pathological phenomenon after trauma, infection, tumor growth, or obstruction of blood supply, and it also can be fatal or lead to long-term disability, psychiatric disorders, substance abuse, or self-harm [1,2]. One exciting possibility would be to control excessive water accumulation in cells. However, all trials that inhibit water channel protein failed in clinic. A recent study by Kitchen et al. [3] reported that targeting the astrocytes' surface localization of water channel protein aquaporin-4(AQP4) significantly relieves CNS edema. Astrocytes are the most abundant cell type of the brain and generally have a greater capacity than neurons to survive stresses [4]. Astrocyte cell function is critically affected by the lack of oxygen supply(hypoxia) to the brain, which is usually associated with CNS edema [5]. Their work holds new promise for our ability to use water-transfer strategies to treat CNS edema. Cytotoxic and vasogenic edema are primary interrelated etiological factors for the progress of CNS edema [6]. Vasogenic edema also depends on the extent of cytotoxic edema and the nature/severity of the underlying cause of the cytotoxic edema. So, understanding the pathogenesis of cytotoxic edema is important for the treatment of CNS edema. Aquaporins(AQPs) are historically known to be passive transporters of water. Lines of evidence in the last decade have highlighted the diverse function of AQPs beyond water homeostasis, including regulation of renal water balance, brain-fluid homeostasis, triglyceride cycling, and skin hydration [7]. Moreover, a subgroup of AQP water channels, termed ‘aquaglyceroporins', also facilitates transmembrane diffusion of small, polar solutes not only water but also solutes [8,9]. AQP4 is the major subtype of AQPs expressed in astrocytes throughout the nervous system and facilitates astroglial cell migration via increasing plasma membrane water permeability, which in turn upregulates the transmembrane water fluxes during astroglial cell movement and is thus considered as an interesting therapeutic target in various neurological disorders. Astrocyte swellingmay also cause cytotoxic component disruptions of the blood-brain barrier, suggesting that astrocytes seem so sensitive to cytotoxic edema. AQP4 is a recognized contributor for the formation of cytotoxic brain edema, which is mainly a phenomenon of intracellular swelling of astrocytes. Knockdown of ‘AQP4' or removal of the perivascular AQP4 pool by α-syntrophin or α-syntrophin deletion has been convincingly proven to counteract osmotically induced acute brain edema following ischemia and other brain injuries [10-12]. A previous study revealed that the NH_2-cytosolic terminus of AQP4 interacts with metabotropic glutamate receptor 5 and assembles with the catalytic subunit of Na,K-ATPase to form a complex that has the potential function for the regulation of water permeability and potassium homeostasis in the astrocytes [13](Fig. 1). In addition, AQP4 may trigger astrocytic Ca~(2+) responses, which is partly dependent on autocrine purinergic signaling(P2 purinergic receptor) activation in response to hypoosmotic stress [14](Fig. 1). Additionally, subcellular relocalization of AQP4 in primary astrocytes is induced by calmodulin(CaM), calcium, and PKA in response to hypotonicity [15]. Further study proved that hypoxia-driven astrocyte swelling induces the increased abundance of AQP4 and initiates AQP4 cellsurface relocalization in a CaM-and PKA-dependent manner [3](Fig. 1).