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

Wagner, Kim A.; Unger, Lucas; Salman, Mootaz M.; Kitchen, Philip; Bill, Roslyn M.; Yool, Andrea J.

doi:10.3390/ijms23031388

Cited by 72 publications

(59 citation statements)

References 576 publications

(706 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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“…This mislocalization can be a potential therapeutic target ( Ciappelloni et al, 2019 ). 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 ).…”

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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“…Although not discussed in this review, it is important to understand that complex molecular and signaling mechanisms of AQP4 exists and that their regulation is highly dynamic and intricate. For the purposes of novel drug discovery, one could explore the different steps involving AQP4 trafficking and recycling as well as the intracellular signals that modulate AQP4 activity (Markou et al, 2022 ; Salman et al, 2022b ; Wagner et al, 2022 ). Moreover, gating mechanisms of AQP4 should also be considered, rather than mere redistribution.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy

Szu

Binder

2022

Front. Cell. Neurosci.

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Epilepsy is a chronic brain disorder characterized by unprovoked seizures. Mechanisms underlying seizure activity have been intensely investigated. Alterations in astrocytic channels and transporters have shown to be a critical player in seizure generation and epileptogenesis. One key protein involved in such processes is the astrocyte water channel aquaporin-4 (AQP4). Studies have revealed that perivascular AQP4 redistributes away from astrocyte endfeet and toward the neuropil in both clinical and preclinical studies. This subcellular mislocalization significantly impacts neuronal hyperexcitability and understanding how AQP4 becomes dysregulated in epilepsy is beginning to emerge. In this review, we evaluate the role of AQP4 dysregulation and mislocalization in epilepsy.

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

Cited by 72 publications

References 576 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

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

Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy

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