Differential Expression of Aquaporins in Experimental Models of Acute Lung Injury

Vassiliou, Alice G.; Kardara, Matina; Maniatis, Nikolaos A.; Orfanos, Stylianos E.; Κοτανίδου, Αναστασία

doi:10.21873/invivo.11143

Cited by 15 publications

(10 citation statements)

References 52 publications

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“…While AQP5 knock-out mice have no discernable difference in baseline phenotype, changes in AQP5 have been implicated in the pathogenesis of acute lung injury, as well as in the development of xerostomia, lung submucosal glandular secretions, and in the regulation of sweat ( Song and Verkman, 2001 ; Verkman, 2007 ; Inoue, 2016 ; Zhang J. et al, 2018 ; Hosoi et al, 2020 ). Additionally, AQP5 expression is regulated by a number of transcriptional and post-translational mechanisms, including inflammatory signals ( Towne et al, 2000 ; Towne et al, 2001 ; Hasan et al, 2014 ; Vassiliou et al, 2017 ), cAMP ( Yang et al, 2003 ), hypoxia, ( Kawedia et al, 2013 ), shear stress ( Sidhaye et al, 2008 ), and tonicity ( Sidhaye et al, 2006 ). Here we use a novel high-throughput screening approach based on AQP5 abundance to identify repurposed drugs that increased AQP5.…”

Section: Discussionmentioning

confidence: 99%

“…AQP5 is implicated in the development of acute lung injury, and genetic polymorphisms in the AQP5 promoter have been associated with clinical outcomes in critically ill humans ( Rump et al, 2016 ). Preclinical models of murine acute lung injury show a pattern where AQP5 protein abundance is reduced in the lung following injury ( Towne et al, 2000 ; Hasan et al, 2014 ; Vassiliou et al, 2017 ; Zhang J. et al, 2018 ), and some studies suggest restoring its expression could be protective ( Jiang et al, 2015 ). AQP5 deficiency has also been implicated in preclinical models of xerostomia, sialadenitis, and Sjogren’s syndrome, and restoration of aquaporin channels in these tissues is associated with increased saliva secretion ( Lai et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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A Repurposed Drug Screen for Compounds Regulating Aquaporin 5 Stability in Lung Epithelial Cells

et al. 2022

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Aquaporin 5 (AQP5) is expressed in several cell types in the lung and regulates water transport, which contributes to barrier function during injury and the composition of glandular secretions. Reduced AQP5 expression is associated with barrier dysfunction during acute lung injury, and strategies to enhance its expression are associated with favorable phenotypes. Thus, pharmacologically enhancing AQP5 expression could be beneficial. Here, we optimized a high-throughput assay designed to detect AQP5 abundance using a cell line stably expressing bioluminescent-tagged AQP5. We then screened a library of 1153 compounds composed of FDA-approved drugs for their effects on AQP5 abundance. We show compounds Niclosamide, Panobinostat, and Candesartan Celexitil increased AQP5 abundance, and show that Niclosamide has favorable cellular toxicity profiles. We determine that AQP5 levels are regulated in part by ubiquitination and proteasomal degradation in lung epithelial cells, and mechanistically Niclosamide increases AQP5 levels by reducing AQP5 ubiquitination and proteasomal degradation. Functionally, Niclosamide stabilized AQP5 levels in response to hypotonic stress, a stimulus known to reduce AQP5 levels. In complementary assays, Niclosamide increased endogenous AQP5 in both A549 cells and in primary, polarized human bronchial epithelial cells compared to control-treated cells. Further, we measured rapid cell volume changes in A549 cells in response to osmotic stress, an effect controlled by aquaporin channels. Niclosamide-treated A549 cell volume changes occurred more rapidly compared to control-treated cells, suggesting that increased Niclosamide-mediated increases in AQP5 expression affects functional water transport. Taken together, we describe a strategy to identify repurposed compounds for their effect on AQP5 protein abundance. We validated the effects of Niclosamide on endogenous AQP5 levels and in regulating cell-volume changes in response to tonicity changes. Our findings highlight a unique approach to screen for drug effects on protein abundance, and our workflow can be applied broadly to study compound effects on protein abundance in lung epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Repurposed Drug Screen for Compounds Regulating Aquaporin 5 Stability in Lung Epithelial Cells

et al. 2022

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“…AQPs are present in different cells and organs, and based on results provided by experimental animal models, they might have a relevant action in the pathogenesis of acute and chronic pulmonary diseases [ 21 , 22 , 23 ], and acute renal failure [ 24 ].…”

Section: General Considerations On Aquaporinsmentioning

confidence: 99%

Critical Role of Aquaporins in Cancer: Focus on Hematological Malignancies

Allegra

Cicero

Mirabile

et al. 2022

Cancers

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Aquaporins are transmembrane molecules regulating the transfer of water and other compounds such as ions, glycerol, urea, and hydrogen peroxide. Their alteration has been reported in several conditions such as cancer. Tumor progression might be enhanced by aquaporins in modifying tumor angiogenesis, cell volume adaptation, proteases activity, cell–matrix adhesions, actin cytoskeleton, epithelial–mesenchymal transitions, and acting on several signaling pathways facilitating cancer progression. Close connections have also been identified between the aquaporins and hematological malignancies. However, it is difficult to identify a unique action exerted by aquaporins in different hemopathies, and each aquaporin has specific effects that vary according to the class of aquaporin examined and to the different neoplastic cells. However, the expression of aquaporins is altered in cell cultures and in patients with acute and chronic myeloid leukemia, in lymphoproliferative diseases and in multiple myeloma, and the different expression of aquaporins seems to be able to influence the efficacy of treatment and could have a prognostic significance, as greater expression of aquaporins is correlated to improved overall survival in leukemia patients. Finally, we assessed the possibility that modifying the aquaporin expression using aquaporin-targeting regulators, specific monoclonal antibodies, and even aquaporin gene transfer could represent an effective therapy of hematological malignancies.

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“…Интенсивность экспрессии гена AQ1 не менялась во всех моделях, в то время как в отношении AQ9 этот показатель увеличивался в моделях с использованием ЛПС и при ВИПЛ. Авторы предположили, что степень участия аквапоринов в механизмах развития ОРДС зависит от этиологического фактора, несмотря на то что все модели были индуцированы прямыми повреждающими воздействиями [36].…”

Section: нейтрофильные гранулоциты и их роль в инициальные стадии ордсunclassified

Molecular and cellular bases for the pathogenesis of acute respiratory distress syndrome. Current approaches to pathogenetic therapy

Пугач¹,

Чепур²,

Тюнин³

et al. 2022

Nauchno-Prakticheskii Zhurnal «Patogenez»

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В литературном обзоре приведены современные представления о патогенезе и подходах к патогенетической терапии острого респираторного дистресс-синдрома. Рассмотрены механизмы активации нейтрофилов в ранние стадии развития этого синдрома и вклад нейтрофильных внеклеточных ловушек в прогрессирование воспалительных процессов. Показана важность дестабилизации межклеточных контактов эндотелия сосудов и альвеолярного эпителия в инициации отёка лёгких, а также роль эпителиальных натриевых каналов и аквапоринов на этапе резорбции альвеолярной жидкости при переходе в пролиферативную стадию синдрома. Отмечен вклад липидных противовоспалительных медиаторов в механизмах разрешения воспаления. Проанализированы результаты опубликованных экспериментальных и клинических исследований, подчеркивающих актуальность поиска новых стратегий фармакологического воздействия на основные звенья патогенеза этого жизнеугрожающего состояния. Описаны современные возможности патогенетической терапии, направленной на снижение нейтрофил-опосредованного повреждения ткани лёгких, уменьшение проницаемости аэрогематического барьера, а также восстановление структурной целостности и нормального клеточного состава легочной ткани. This review presents current concepts on the pathogenesis and approaches to pathogenetic therapy of acute respiratory distress syndrome. The authors addressed mechanisms of early neutrophil activation and the contribution of neutrophil extracellular traps to the progression of inflammatory processes. The review focused on the importance of destabilizing endothelial and alveolar epithelial intercellular junctions for initiation of pulmonary edema, as well as on the role of epithelial sodium channels and aquaporins at the stage of alveolar fluid resorption during the proliferative stage of the syndrome. The contribution of lipid anti-inflammatory mediators to the mechanisms of inflammation resolution was emphasized. The article analyzed results of published experimental and clinical studies that stressed the relevance of searching for new strategies of pharmacological interference with major steps in the pathogenesis of this life-threatening condition. The current capabilities of pathogenetic therapy were described that are aimed at reducing the neutrophil-mediated damage of lung tissue, at decreasing the permeability of the air-blood barrier, and at restoring the structural integrity and normal cellular composition of the lung tissue.

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Differential Expression of Aquaporins in Experimental Models of Acute Lung Injury

Cited by 15 publications

References 52 publications

A Repurposed Drug Screen for Compounds Regulating Aquaporin 5 Stability in Lung Epithelial Cells

A Repurposed Drug Screen for Compounds Regulating Aquaporin 5 Stability in Lung Epithelial Cells

Critical Role of Aquaporins in Cancer: Focus on Hematological Malignancies

Molecular and cellular bases for the pathogenesis of acute respiratory distress syndrome. Current approaches to pathogenetic therapy

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