Modulating the water channel AQP4 alters miRNA expression, astrocyte connectivity and water diffusion in the rodent brain

Jullienne, A.; Fukuda, Andrew M.; Ichkova, Aleksandra; Nishiyama, Nina C.; Aussudre, Justine; Obenaus, André; Badaut, Jérôme

doi:10.1038/s41598-018-22268-y

Cited by 21 publications

(26 citation statements)

References 42 publications

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“…Knockdown of rat AQP4 (rAQP4) gene expression in vivo and mouse AQP4 (mAQP4) gene expression in vitro was shown to result in a significant increase in miR-224, which targets not only AQP4 but also gap junction protein connexin 43 (Cx43), which is one of the two primary proteins which form gap junction channels between astrocytes [48]. Knockdown of Cx43 resulted not only in a significant increase in miR-224 expression, but also in miR-19a, which also targets both proteins [48], implying that miR-19a and miR-224 may have important roles in the regulation of not only astrocyte connectivity but also water permeability. MiR-29b, which was already known to be downregulated in ischemic stroke, was shown to have a direct effect on expression of mAQP4 [49].…”

Section: Translational Regulation Of Aqp4mentioning

confidence: 99%

Regulation of AQP4 in the Central Nervous System

Vandebroek

Yasui

2020

IJMS

106

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Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.

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Section: Translational Regulation Of Aqp4mentioning

confidence: 99%

Regulation of AQP4 in the Central Nervous System

Vandebroek

Yasui

2020

IJMS

106

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“…AQP4 is the main water channel expressed in the CNS and is found at highest concentration in astrocyte end-feet, which together with blood vessels form the blood–brain barrier (BBB) [13,69]. AQP4 expression is increased in cerebral edema and ischemia.…”

Section: Aquaporin Functionmentioning

confidence: 99%

Inhibitors of Mammalian Aquaporin Water Channels

Abir-Awan

Kitchen

Salman

et al. 2019

IJMS

101

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Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need.

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“…AQP4 and gap junctions are physically very close together (Rash et al, ) and the regulation of AQP4 with miRNA can affect the level of expression of Cx43, a protein involved in the formation of the gap junctions and can contribute to the diffusion of water and solutes within the astrocytic network (Jullienne et al, ). This co‐regulation of AQP4 and Cx43 expressions raised the question of their implications in the pathophysiological processes.…”

Section: Role Of Aqps In Edema Processmentioning

confidence: 99%

Aquaporins in brain edema

Clément

Rodriguez‐Grande

Badaut

2018

J of Neuroscience Research

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Brain edema is a common feature of brain injuries, which leads to increased intracranial pressure (ICP) and ischemia that worsen outcome. Current management of edema focuses on reduction of ICP, but there are no treatments targeting the molecular players directly involved in edema process. The perivascular astrocyte endfeet are critical in maintaining brain homeostasis with ionic and water exchange; in this context, aquaporins (AQPs), astrocyte water channels, have emerged as privileged targets for edema modulation. However, AQPs can facilitate either accumulation or drainage of water, depending on the osmotic gradients between extra‐intracellular space; and thus inhibition of AQPs leads to different outcomes depending on specific tissue characteristics and time post‐injury. Most of this knowledge has been gathered from the study of AQP4, the best characterized AQP and the one that has the biggest impact on water movement. In addition to the level of expression, the ratio of AQP4 isoforms (m1, m23 or mz), the spatial distribution of AQP4 into orthogonal arrays of particles, and the interaction of AQP4 with neighboring ionic channels and gap junctions could directly impact edema formation. Although there are no specific AQP4 pharmacological blockers, the development of AQP4 siRNA offers a promising therapeutic tool. Given the complex dynamics of AQP4, therapies targeting AQP4 should carefully take into account the particular features of the injury (e.g., hemorrhagic vs. non‐hemorrhagic) and different times after injury (e.g., phase of edema formation vs. resolution).

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Modulating the water channel AQP4 alters miRNA expression, astrocyte connectivity and water diffusion in the rodent brain

Cited by 21 publications

References 42 publications

Regulation of AQP4 in the Central Nervous System

Regulation of AQP4 in the Central Nervous System

Inhibitors of Mammalian Aquaporin Water Channels

Aquaporins in brain edema

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