Dynamic regulation of aquaporin-4 water channels in neurological disorders

Abstract

Aquaporin-4 water channels play a central role in brain water regulation in neurological disorders. Aquaporin-4 is abundantly expressed at the astroglial endfeet facing the cerebral vasculature and the pial membrane, and both its expression level and subcellular localization significantly influence brain water transport. However, measurements of aquaporin-4 levels in animal models of brain injury often report opposite trends of change at the injury core and the penumbra. Furthermore, aquaporin-4 channels play a beneficial role in brain water clearance in vasogenic edema, but a detrimental role in cytotoxic edema and exacerbate cell swelling. In light of current evidence, we still do not have a complete understanding of the role of aquaporin-4 in brain water transport. In this review, we propose that the regulatory mechanisms of aquaporin-4 at the transcriptional, translational, and post-translational levels jointly regulate water permeability in the short and long time scale after injury. Furthermore, in order to understand why aquaporin-4 channels play opposing roles in cytotoxic and vasogenic edema, we discuss experimental evidence on the dynamically changing osmotic gradients between blood, extracellular space, and the cytosol during the formation of cytotoxic and vasogenic edema. We conclude with an emerging picture of the distinct osmotic environments in cytotoxic and vasogenic edema, and propose that the directions of aquaporin-4-mediated water clearance in these two types of edema are distinct. The difference in water clearance pathways may provide an explanation for the conflicting observations of the roles of aquaporin-4 in edema resolution.

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…In addition, a transparenchymal flow of ISF, solutes, and waste would appear difficult to reconcile with the required homeostasis of the brain microenvironment for synaptic transmission. Aquaporins clearly do play diverse roles in brain water balance in health and disease [9,84] and such concepts have undoubtedly informed the 'glymphatic' hypothesis. The previous studies performed on AQP4-deficient mice have demonstrated that such animals exhibit an increased brain ECS volume fraction [196], increased basal brain water content [73], and larger intracranial pressure elevations in response to induced vasogenic (non-cellular) oedema [134], suggesting that AQP4 indeed plays critical roles in the transport of water between brain compartments as well as the formation and resolution of oedema.…”

Hydrocephalus: the role of cerebral aquaporin-4 channels and computational modeling considerations of cerebrospinal fluid

“…Neurological disease processes such as hydrocephalus may involve the dysregulation of AQP4 signaling pathways-a product of a combination of transcriptional events and pathways, as depicted in a signaling map by Hsu et al 53 After the translation process, phosphorylation of several amino acid residues on the polypeptide chain is required for the correct trafficking, expression, and membrane targeting of AQP4, as well as for its assembly into higher-order arrays. The phosphorylation of AQP4 can effectively and rapidly change membrane water permeability through either endocytosis of the water channels or the disruption of square array formation.…”

“…As previously mentioned, numerous studies have shown upregulation of AQP4 expression in hydrocephalic states. Regulatory mechanisms of AQP4 and its role in neurological diseases were recently reviewed by Hsu et al 53 Transcription factors capable of activating the Aqp4 gene may play an important role in the regulation of AQP4 expression in neurological disorders; in oxidative stress, it has been elucidated that gene nuclear factor (erythroid-derived 2) -like 2 (Nrf2) activates AQP4.…”

“…AQP4 channels are present throughout the brain, specifically concentrated in the end-feet of astrocytes and in the glia limitans interna and externa. 15,53,92 They passively respond to osmotic gradients and play roles in fluid secretion, cell migration, brain edema, metabolism, and many aspects of cell homeostasis. 135 In addition to their role in brain water transport, AQP4 channels have also been increasingly linked to clearance of ions, metabolites, and even soluble proteins.…”

“…10,45,53,91,121 Therefore, we have attempted to summarize relevant knowledge of molecular mechanisms of water exchange through AQP4 channels. We begin with an analysis of the current research on the relationship of AQP4 to hydrocephalus, followed by an overview of AQP4 isoforms, promoters, transcription factors, and posttranslational modification.…”