Molecular mechanisms governing aquaporin relocalisation

Markou, Andrea; Unger, Lucas; Abir-Awan, Mohammed; Saadallah, Ahmed; Halsey, Andrea; Baklava, Zita; Conner, Matthew T.; Törnroth-Horsefield, Susanna; Greenhill, Stuart; Conner, Alex C.; Bill, Roslyn M.; Salman, Mootaz M.; Kitchen, Philip

doi:10.1016/j.bbamem.2021.183853

Cited by 63 publications

(48 citation statements)

References 165 publications

(197 reference statements)

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“…TFP, a calmodulin inhibitor, was effectively shown to reduce cerebral edema by inhibiting aquaporin-4 (AQP4) localization [ 36 , 37 ]. Although the detailed molecular mechanism of brain water transport is lacking, AQP4 was implicated as a key determinant in the lymphatic system and, therefore, a potential therapeutic target for brain disorders presenting edema [ 38 , 39 , 40 , 41 , 42 ]. As mentioned, CSVD is characterized by various manifestations that can be utilized as therapeutic candidates to be evaluated using evolving approaches for drug discovery and development.…”

Section: Discussionmentioning

confidence: 99%

A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress

Guy

Volkman

Wilczynski

et al. 2022

IJMS

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Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. Manifestations of CSVD include cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models have been found to reproduce most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. Here, we described a novel model for CSVD using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y), which display chronic hypertension and enhanced peripheral oxidative stress. SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham-operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex vivo MRI and biochemical and histological analyses. SBH/y-DOCA rats show a neurological decline and cognitive impairment and present multiple cerebrovascular pathologies associated with CSVD, such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models. Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for testing novel therapeutics.

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Section: Discussionmentioning

confidence: 99%

A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress

Guy

Volkman

Wilczynski

et al. 2022

IJMS

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“…AQP8 is expressed in the inner membrane of mitochondria and involved in H 2 O 2 transport linked with the accumulation of reactive oxygen species (ROS) [52], revealing an unexpected breadth of physiologically important roles for AQPs across phyla [13,56] and highlighting many gaps in our knowledge that are yet to be addressed. Recent perspectives have provided comprehensive synopses of AQP-related diseases beyond the scope of this review [57][58][59][60][61][62][63][64][65][66][67][68].…”

Section: Aqp Permeabilities: An Expanding Repertoirementioning

confidence: 99%

Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease

Wagner

Unger

Salman

et al. 2022

IJMS

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The aquaporins (AQPs) are a family of small integral membrane proteins that facilitate the bidirectional transport of water across biological membranes in response to osmotic pressure gradients as well as enable the transmembrane diffusion of small neutral solutes (such as urea, glycerol, and hydrogen peroxide) and ions. AQPs are expressed throughout the human body. Here, we review their key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis. Evidence from a wide variety of studies now supports a view of the functions of AQPs being much more complex than simply mediating the passive flow of water across biological membranes. The discovery and development of small-molecule AQP inhibitors for research use and therapeutic development will lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders.

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“…Studies have demonstrated that AQPs were involved in human physiology and pathophysiology, such as fluid homeostasis and secretion, signal transduction and sensory functions, defense and metabolism, and motility and cancer ( Wagner et al, 2022 ). Recently, the research and development of drugs targeting AQPs to treat diverse conditions have become a hot topic ( Verkman et al, 2014 ; Abir-Awan et al, 2019 ; Markou et al, 2022 ). Recent breakthroughs indicate that inhibition of hydrogen peroxide permeation through AQP1 provides a new approach to treat hypertrophic cardiomyopathies, and inhibition of AQP4 localization with the licensed drug trifluoperazine provides compelling evidence for a new approach to treating CNS edema ( Salman et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

β-Hydroxybutyrate Attenuates Painful Diabetic Neuropathy via Restoration of the Aquaporin-4 Polarity in the Spinal Glymphatic System

Wang

et al. 2022

Front. Neurosci.

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Waste removal is essential for maintaining homeostasis and the normal function of the central nervous system (CNS). The glymphatic system based on aquaporin-4 (AQP4) water channels on the endfeet of astrocytes is recently discovered as the excretion pathway for metabolic waste products of CNS. In the CNS, α-syntrophin (SNTA1) directly or indirectly anchors AQP4 in astrocyte membranes facing blood vessels. Studies have indicated that β-hydroxybutyrate (BHB) can raise the expression of SNTA1 and thus restoring AQP4 polarity in mice models with Alzheimer’s disease. The study aims to evaluate the neuroprotective mechanism of BHB in rats with painful diabetic neuropathy (PDN). PDN rats were modeled under a high-fat and high-glucose diet with a low dose of streptozotocin. Magnetic resonance imaging (MRI) was applied to observe the clearance of contrast to indicate the functional variability of the spinal glymphatic system. Mechanical allodynia was assessed by paw withdrawal threshold. The expressions of SNTA1 and AQP4 were tested, and the polarity reversal of AQP4 protein was measured. As demonstrated, PDN rats were manifested with deceased contrast clearance of the spinal glymphatic system, enhanced mechanical allodynia, lower expression of SNTA1, higher expression of AQP4, and reversed polarity of AQP4 protein. An opposite change in the above characteristics was observed in rats being treated with BHB. This is the first study that demonstrated the neuroprotective mechanism of BHB to attenuate PDN via restoration of the AQP4 polarity in the spinal glymphatic system and provides a promising therapeutic strategy for PDN.

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Molecular mechanisms governing aquaporin relocalisation

Cited by 63 publications

References 165 publications

A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress

A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress

Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease

β-Hydroxybutyrate Attenuates Painful Diabetic Neuropathy via Restoration of the Aquaporin-4 Polarity in the Spinal Glymphatic System

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