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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 21126

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Dr. Graça Soveral

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Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidaded de Lisboa, Lisbon, Portugal
Interests: water and solute transport; membrane; pathophysiology; metabolism; cancer
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Dr. Inês Vieira Da Silva

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Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
Interests: aquaporin; inflammation; immunology; metabolic diseases
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Special Issue Information

Dear Colleagues,

Aquaporins (AQPs) are involved in many biological functions, including transepithelial fluid transport, cell migration and proliferation, brain oedema and neuroexcitation, adipocyte metabolism and epidermal water retention. In the plant kingdom, aquaporins are key proteins providing strict regulation of water uptake and transport across cellular membranes and tissues at the whole-plant level, regulating plant growth and development. In the last decade, aquaporins have become a hot area of research in molecular cell biology, biochemistry and biophysics, with increasing physiological and medical implications. In addition, human diseases caused by aquaporin dysfunction have unveiled these proteins’ potential as drug targets and opened new perspectives with which to untangle mechanisms of disease.

This Special Issue aims to provide an updated scientific view of the aquaporin field, including structure–function relationships, physiological and chemical regulation, implications in disease and potential as drug targets, creating opportunities for drug development and novel therapies. Authors are invited to submit original research and review papers addressing these topics to this Special Issue.

Dr. Graça Soveral
Dr. Inês Vieira Da Silva
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

aquaporin
membrane channel
regulation
pathophysiology
drug target

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Related Special Issue

New Insights into Aquaporins: 2nd Edition in International Journal of Molecular Sciences (4 articles)

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Research

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16 pages, 3395 KiB

Open AccessArticle

Structural Basis for the Interaction between the Ezrin FERM-Domain and Human Aquaporins

by Helin Strandberg, Carl Johan Hagströmer, Balder Werin, Markus Wendler, Urban Johanson and Susanna Törnroth-Horsefield

Int. J. Mol. Sci. 2024, 25(14), 7672; https://doi.org/10.3390/ijms25147672 - 12 Jul 2024

Viewed by 1275

Abstract

The Ezrin/Radixin/Moesin (ERM) family of proteins act as cross-linkers between the plasma membrane and the actin cytoskeleton. This mechanism plays an essential role in processes related to membrane remodeling and organization, such as cell polarization, morphogenesis and adhesion, as well as in membrane protein trafficking and signaling pathways. For several human aquaporin (AQP) isoforms, an interaction between the ezrin band Four-point-one, Ezrin, Radixin, Moesin (FERM)-domain and the AQP C-terminus has been demonstrated, and this is believed to be important for AQP localization in the plasma membrane. Here, we investigate the structural basis for the interaction between ezrin and two human AQPs: AQP2 and AQP5. Using microscale thermophoresis, we show that full-length AQP2 and AQP5 as well as peptides corresponding to their C-termini interact with the ezrin FERM-domain with affinities in the low micromolar range. Modelling of the AQP2 and AQP5 FERM complexes using ColabFold reveals a common mode of binding in which the proximal and distal parts of the AQP C-termini bind simultaneously to distinct binding sites of FERM. While the interaction at each site closely resembles other FERM-complexes, the concurrent interaction with both sites has only been observed in the complex between moesin and its C-terminus which causes auto-inhibition. The proposed interaction between AQP2/AQP5 and FERM thus represents a novel binding mode for extrinsic ERM-interacting partners. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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20 pages, 10714 KiB

Open AccessArticle

Recovery of Water Homeostasis in Adenine-Induced Kidney Disease Is Mediated by Increased AQP2 Membrane Targeting

by Jasmine C. L. Atay, Søren H. Elsborg, Johan Palmfeldt, Lene N. Nejsum and Rikke Nørregaard

Int. J. Mol. Sci. 2024, 25(6), 3447; https://doi.org/10.3390/ijms25063447 - 19 Mar 2024

Cited by 3 | Viewed by 2165

Abstract

Chronic kidney disease (CKD) represents a major public health burden with increasing prevalence. Current therapies focus on delaying CKD progression, underscoring the need for innovative treatments. This necessitates animal models that accurately reflect human kidney pathologies, particularly for studying potential reversibility and regenerative mechanisms, which are often hindered by the progressive and irreversible nature of most CKD models. In this study, CKD was induced in mice using a 0.2% adenine-enriched diet for 4 weeks, followed by a recovery period of 1 or 2 weeks. The aim was to characterize the impact of adenine feeding on kidney function and injury as well as water and salt homeostasis throughout disease progression and recovery. The adenine diet induced CKD is characterized by impaired renal function, tubular injury, inflammation, and fibrosis. A significant decrease in urine osmolality, coupled with diminished aquaporin-2 (AQP2) expression and membrane targeting, was observed after adenine treatment. Intriguingly, these parameters exhibited a substantial increase after a two-week recovery period. Despite these functional improvements, only partial reversal of inflammation, tubular damage, and fibrosis were observed after the recovery period, indicating that the inclusion of the molecular and structural parameters is needed for a more complete monitoring of kidney status. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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13 pages, 5263 KiB

Open AccessArticle

Evidence That Aquaporin 11 (AQP11) in the Spiny Dogfish (Squalus acanthias) May Represent a Pseudogene

by Christopher P. Cutler, Meghan E. Canicatti and Esosa Omoregie

Int. J. Mol. Sci. 2024, 25(4), 2028; https://doi.org/10.3390/ijms25042028 - 7 Feb 2024

Cited by 1 | Viewed by 1240

Abstract

Various attempts to amplify an AQP11 cDNA from tissues of the spiny dogfish (Squalus acanthias) were made. Two pairs of deoxy-inosine-containing degenerate primers were designed based on conserved amino acid sequences from an AQP11 alignment. These primers yielded some faint bands from gill cDNA that were sequenced. Blast searches with the sequences showed they were not AQP11. An elasmobranch AQP11 nucleotide sequence alignment was produced to identify conserved regions to make further degenerate primers. One primer pair produced a short 148 bp fragment showing particularly strong amplification in gill and intestine. It was sequenced and represented a piece of the AQP11 gene. However, as the fragment may have resulted from contaminating genomic DNA (in total RNA used to make cDNA), 5′ and 3′ RACE were performed to amplify the two ends of the putative cDNA. Furthermore, 5′ and 3′ RACE amplifications depend on the presence of a 5′ cap nucleotide and a poly A tail, respectively on the putative AQP11 mRNA. Hence, successful amplification was only possible from cDNA and not genomic DNA. Nested RACE amplifications were performed using gill and intestinal RACE cDNA, but none of the DNA fragments sequenced were AQP11. Consequently, the spiny dogfish AQP11 gene may represent a pseudogene. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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12 pages, 2049 KiB

Open AccessArticle

AQP3 and AQP9—Contrary Players in Sepsis?

by Patrick Thon, Tim Rahmel, Dominik Ziehe, Lars Palmowski, Britta Marko, Hartmuth Nowak, Alexander Wolf, Andrea Witowski, Jennifer Orlowski, Björn Ellger, Frank Wappler, Elke Schwier, Dietrich Henzler, Thomas Köhler, Alexander Zarbock, Stefan Felix Ehrentraut, Christian Putensen, Ulrich Hermann Frey, Moritz Anft, Nina Babel, Barbara Sitek, Michael Adamzik, Lars Bergmann, Matthias Unterberg, Björn Koos and Katharina Rump Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(2), 1209; https://doi.org/10.3390/ijms25021209 - 19 Jan 2024

Cited by 6 | Viewed by 2297

Abstract

Sepsis involves an immunological systemic response to a microbial pathogenic insult, leading to a cascade of interconnected biochemical, cellular, and organ–organ interaction networks. Potential drug targets can depict aquaporins, as they are involved in immunological processes. In immune cells, AQP3 and AQP9 are of special interest. In this study, we tested the hypothesis that these aquaporins are expressed in the blood cells of septic patients and impact sepsis survival. Clinical data, routine laboratory parameters, and blood samples from septic patients were analyzed on day 1 and day 8 after sepsis diagnosis. AQP expression and cytokine serum concentrations were measured. AQP3 mRNA expression increased over the duration of sepsis and was correlated with lymphocyte count. High AQP3 expression was associated with increased survival. In contrast, AQP9 expression was not altered during sepsis and was correlated with neutrophil count, and low levels of AQP9 were associated with increased survival. Furthermore, AQP9 expression was an independent risk factor for sepsis lethality. In conclusion, AQP3 and AQP9 may play contrary roles in the pathophysiology of sepsis, and these results suggest that AQP9 may be a novel drug target in sepsis and, concurrently, a valuable biomarker of the disease. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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11 pages, 1545 KiB

Open AccessArticle

Toward New AQP4 Inhibitors: ORI-TRN-002

by Michael Thormann, Nadine Traube, Nasser Yehia, Roland Koestler, Gergana Galabova, Nanna MacAulay and Trine L. Toft-Bertelsen

Int. J. Mol. Sci. 2024, 25(2), 924; https://doi.org/10.3390/ijms25020924 - 11 Jan 2024

Cited by 3 | Viewed by 1863

Abstract

Cerebral edema is a life-threatening condition that can cause permanent brain damage or death if left untreated. Existing therapies aim at mitigating the associated elevated intracranial pressure, yet they primarily alleviate pressure rather than prevent edema formation. Prophylactic anti-edema therapy necessitates novel drugs targeting edema formation. Aquaporin 4 (AQP4), an abundantly expressed water pore in mammalian glia and ependymal cells, has been proposed to be involved in cerebral edema formation. A series of novel compounds have been tested for their potential inhibitory effects on AQP4. However, selectivity, toxicity, functional inhibition, sustained therapeutic concentration, and delivery into the central nervous system are major challenges. Employing extensive density-functional theory (DFT) calculations, we identified a previously unreported thermodynamically stable tautomer of the recently identified AQP4-specific inhibitor TGN-020 (2-(nicotinamide)-1,3,4-thiadiazol). This novel form, featuring a distinct hydrogen-bonding pattern, served as a template for a COSMOsim-3D-based virtual screen of proprietary compounds from Origenis™. The screening identified ORI-TRN-002, an electronic homologue of TGN-020, demonstrating high solubility and low protein binding. Evaluating ORI-TRN-002 on AQP4-expressing Xenopus laevis oocytes using a high-resolution volume recording system revealed an IC₅₀ of 2.9 ± 0.6 µM, establishing it as a novel AQP4 inhibitor. ORI-TRN-002 exhibits superior solubility and overcomes free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising anti-edema therapy for treating cerebral edema in the future. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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14 pages, 4009 KiB

Open AccessArticle

Methazolamide Reduces the AQP5 mRNA Expression and Immune Cell Migration—A New Potential Drug in Sepsis Therapy?

by Katharina Rump, Björn Koos, Dominik Ziehe, Patrick Thon, Tim Rahmel, Lars Palmowski, Britta Marko, Alexander Wolf, Andrea Witowski, Zainab Bazzi, Maha Bazzi, Jennifer Orlowski, Michael Adamzik, Lars Bergmann and Matthias Unterberg

Int. J. Mol. Sci. 2024, 25(1), 610; https://doi.org/10.3390/ijms25010610 - 3 Jan 2024

Cited by 4 | Viewed by 1690

Abstract

Sepsis is a life-threatening condition caused by the dysregulated host response to infection. Novel therapeutic options are urgently needed and aquaporin inhibitors could suffice as aquaporin 5 (Aqp5) knockdown provided enhanced sepsis survival in a murine sepsis model. Potential AQP5 inhibitors provide sulfonamides and their derivatives. In this study, we tested the hypothesis that sulfonamides reduce AQP5 expression in different conditions. The impact of sulfonamides on AQP5 expression and immune cell migration was examined in cell lines REH and RAW 264.7 by qPCR, Western blot and migration assay. Subsequently, whether furosemide and methazolamide are capable of reducing AQP5 expression after LPS incubation was investigated in whole blood samples of healthy volunteers. Incubation with methazolamide (10⁻⁵ M) and furosemide (10⁻⁶ M) reduced AQP5 mRNA and protein expression by about 30% in REH cells. Pre-incubation of the cells with methazolamide reduced cell migration towards SDF1-α compared to non-preincubated cells to control level. Pre-incubation with methazolamide in PBMCs led to a reduction in LPS-induced AQP5 expression compared to control levels, while furosemide failed to reduce it. Methazolamide appears to reduce AQP5 expression and migration of immune cells. However, after LPS administration, the reduction in AQP5 expression by methazolamide is no longer possible. Hence, our study indicates that methazolamide is capable of reducing AQP5 expression and has the potential to be used in sepsis prophylaxis. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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Review

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18 pages, 1634 KiB

Open AccessReview

Peroxiporins and Oxidative Stress: Promising Targets to Tackle Inflammation and Cancer

by Inês V. da Silva, Monika Mlinarić, Ana Rita Lourenço, Olivia Pérez-Garcia, Ana Čipak Gašparović and Graça Soveral

Int. J. Mol. Sci. 2024, 25(15), 8381; https://doi.org/10.3390/ijms25158381 - 1 Aug 2024

Cited by 8 | Viewed by 2101

Abstract

Peroxiporins are a specialized subset of aquaporins, which are integral membrane proteins primarily known for facilitating water transport across cell membranes. In addition to the classical water transport function, peroxiporins have the unique capability to transport hydrogen peroxide (H₂O₂), a reactive oxygen species involved in various cellular signaling pathways and regulation of oxidative stress responses. The regulation of H₂O₂ levels is crucial for maintaining cellular homeostasis, and peroxiporins play a significant role in this process by modulating its intracellular and extracellular concentrations. This ability to facilitate the passage of H₂O₂ positions peroxiporins as key players in redox biology and cellular signaling, with implications for understanding and treating various diseases linked to oxidative stress and inflammation. This review provides updated information on the physiological roles of peroxiporins and their implications in disease, emphasizing their potential as novel biomarkers and drug targets in conditions where they are dysregulated, such as inflammation and cancer. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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13 pages, 860 KiB

Open AccessReview

Application of Aquaporins as Markers in Forensic Pathology: A Systematic Review of the Literature

by Letizia Alfieri, Angelo Montana, Paolo Frisoni, Stefano D’Errico and Margherita Neri

Int. J. Mol. Sci. 2024, 25(5), 2664; https://doi.org/10.3390/ijms25052664 - 25 Feb 2024

Cited by 3 | Viewed by 1779

Abstract

The study of aquaporins (AQPs) in various forensic fields has offered a promising horizon in response to the need to have reliable elements for the identification of the manner of death and for the individuation of forensic markers for the timing of lesions and vitality of injury. In the literature, various tissues have been studied; the most investigated are the lungs, brain, kidneys, skin, and blood vessels. A systematic literature review on PubMed following PRISMA 2020 guidelines enabled the identification of 96 articles. In all, 34 of these were enrolled to identify Aquaporin-like (AQP-like) forensic markers. The analysis of the literature demonstrated that the most significant markers among the AQPs are as follows: for the brain, AQP4, which is very important in brain trauma and hypoxic damage; AQP3 in the skin lesions caused by various mechanisms; and AQP5 in the diagnosis of drowning. Other applications are in organ damage due to drug abuse and thrombus dating. The focus of this review is to collect all the data present in the literature about the forensic application of AQPs as forensic markers in the most important fields of application. In the current use, the individuation, validation, and application of markers in forensic investigation are very useful in real forensic applications in cases evaluated in court. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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22 pages, 856 KiB

Open AccessReview

Aquaporin-4 and Parkinson’s Disease

by Ksenia V. Lapshina and Irina V. Ekimova

Int. J. Mol. Sci. 2024, 25(3), 1672; https://doi.org/10.3390/ijms25031672 - 30 Jan 2024

Cited by 8 | Viewed by 3255

Abstract

The water-selective channel aquaporin-4 (AQP4) is implicated in water homeostasis and the functioning of the glymphatic system, which eliminates various metabolites from the brain tissue, including amyloidogenic proteins. Misfolding of the α-synuclein protein and its post-translational modifications play a crucial role in the development of Parkinson’s disease (PD) and other synucleopathies, leading to the formation of cytotoxic oligomers and aggregates that cause neurodegeneration. Human and animal studies have shown an interconnection between AQP4 dysfunction and α-synuclein accumulation; however, the specific role of AQP4 in these mechanisms remains unclear. This review summarizes the current knowledge on the role of AQP4 dysfunction in the progression of α-synuclein pathology, considering the possible effects of AQP4 dysregulation on brain molecular mechanisms that can impact α-synuclein modification, accumulation and aggregation. It also highlights future directions that can help study the role of AQP4 in the functioning of the protective mechanisms of the brain during the development of PD and other neurodegenerative diseases. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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15 pages, 1455 KiB

Open AccessReview

Aquaporin Expression and Regulation in Clinical and Experimental Sepsis

by Nikolaos S. Lotsios, Chrysi Keskinidou, Ioanna Dimopoulou, Anastasia Kotanidou, Stylianos E. Orfanos and Alice G. Vassiliou

Int. J. Mol. Sci. 2024, 25(1), 487; https://doi.org/10.3390/ijms25010487 - 29 Dec 2023

Cited by 3 | Viewed by 2251

Abstract

Sepsis is an inflammatory disorder caused by the host’s dysfunctional response to infection. Septic patients present diverse clinical characteristics, and in the recent years, it has been the main cause of death in intensive care units (ICU). Aquaporins, membrane proteins with a role in water transportation, have been reported to participate in numerous biological processes. Their role in sepsis progression has been studied extensively. This review aims to examine recent literature on aquaporin expression and regulation in clinical sepsis, as well as established experimental models of sepsis. We will present how sepsis affects aquaporin expression at the molecular and protein level. Moreover, we will delve into the importance of aquaporin regulation at transcriptional, post-transcriptional, translational, and post-translational levels in sepsis by presenting data on aquaporin regulation by non-coding RNAs and selected chemical molecules. Finally, we will focus on the importance of aquaporin single-nucleotide polymorphisms in the setting of sepsis. Full article

(This article belongs to the Special Issue New Insights into Aquaporins)

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