Aquaporin-4: A Potential Therapeutic Target for Cerebral Edema

Abstract

Aquaporin-4 (AQP4) is a family member of water-channel proteins and is dominantly expressed in the foot process of glial cells surrounding capillaries. The predominant expression at the boundaries between cerebral parenchyma and major fluid compartments suggests the function of aquaporin-4 in water transfer into and out of the brain parenchyma. Accumulating evidences have suggested that the dysregulation of aquaporin-4 relates to the brain edema resulting from a variety of neuro-disorders, such as ischemic or hemorrhagic stroke, trauma, etc. During edema formation in the brain, aquaporin-4 has been shown to contribute to the astrocytic swelling, while in the resolution phase, it has been seen to facilitate the reabsorption of extracellular fluid. In addition, aquaporin-4-deficient mice are protected from cytotoxic edema produced by water intoxication and brain ischemia. However, aquaporin-4 deletion exacerbates vasogenic edema in the brain of different pathological disorders. Recently, our published data showed that the upregulation of aquaporin-4 in astrocytes probably contributes to the transition from cytotoxic edema to vasogenic edema. In this review, apart from the traditional knowledge, we also introduce our latest findings about the effects of mesenchymal stem cells (MSCs) and microRNA-29b on aquaporin-4, which could provide powerful intervention tools targeting aquaporin-4.

Regulation of AQP4 in the Central Nervous System

“…AQP4 expression and activity in various neurological disorders has been examined, and several intriguing discoveries have been made. In cerebral edema and ischemia, AQP4 expression is increased [15,16], and inhibition of AQP4 activity, either by knockout or pretreatment with an inhibitor has been shown to cause a reduction in edema size and formation [7,[17][18][19]. However, in vasogenic edema the loss of AQP4 activity actually aggravates the condition, due to the loss of ability to remove excess water from the brain tissue [2,5,16].…”

“…In cerebral edema and ischemia, AQP4 expression is increased [15,16], and inhibition of AQP4 activity, either by knockout or pretreatment with an inhibitor has been shown to cause a reduction in edema size and formation [7,[17][18][19]. However, in vasogenic edema the loss of AQP4 activity actually aggravates the condition, due to the loss of ability to remove excess water from the brain tissue [2,5,16]. In glioblastomas and astrocytomas, AQP4 is upregulated and redistributed, showing a loss of polarized distribution in the end-feet of high grade tumors [12,[20][21][22].…”

“…Finally, AQP4 has been shown to have many roles in Alzheimer's disease, including possibly mediating the clearance of amyloid-β [36][37][38][39], and AQP4 deficiency leads to impaired learning and memory via disruption of both the glutamate transport pathway and K + ion homeostasis [40][41][42][43]. With the increase in interest in AQP4 as a potential therapeutic target [1,5,16,19], and the implications AQP4 activity has on many neurological disorders [7,14,[16][17][18][21][22][23]25,[30][31][32][33][34]42,43], it is important to have a clear understanding of the myriad of ways in which AQP4 is known to be regulated.…”

Involvement of p38 mitogen‐activated protein kinase in altered expressions of AQP1 and AQP4 after carbon monoxide poisoning in rat astrocytes

“…AQP4, the most abundant water channel in the central nervous system, is mainly expressed in ependymal cells and end feet of astrocytic . AQP4 regulates swelling of astrocytes in the acute phase of oedema formation, while it also facilitates the reabsorption of extracellular fluid in the resolution phase . In an acute ischaemic stroke model, the cerebral oedema and hemispheric enlargement at 24 hours were remarkably reduced in AQP4 knock out (KO) mice .…”

“…24,25 AQP4 regulates swelling of astrocytes in the acute phase of oedema formation, while it also facilitates the reabsorption of extracellular fluid in the resolution phase. 26,27 In an acute ischaemic stroke model, the cerebral oedema and hemispheric enlargement at 24 hours were remarkably reduced in AQP4 knock out (KO) mice. 28,29 However, to our knowledge, the roles of AQP1 and AQP4 have not been examined in CO poisoning models.…”