Role of aquaporins in brain water transport and edema

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.

Keywords: aquaporins; brain edema; cytotoxic; hydrocephalus; vasogenic; water channels; water transport.

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).

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.

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.

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.