International Journal of Molecular Sciences

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17 pages, 4836 KiB

Open AccessArticle

Modulation of Membrane Trafficking of AQP5 in the Lens in Response to Changes in Zonular Tension Is Mediated by the Mechanosensitive Channel TRPV1

by Rosica S. Petrova, Nikhil Nair, Nandini Bavana, Yadi Chen, Kevin L. Schey and Paul J. Donaldson

Int. J. Mol. Sci. 2023, 24(10), 9080; https://doi.org/10.3390/ijms24109080 - 22 May 2023

Cited by 2 | Viewed by 1157

Abstract

In mice, the contraction of the ciliary muscle via the administration of pilocarpine reduces the zonular tension applied to the lens and activates the TRPV1-mediated arm of a dual feedback system that regulates the lens’ hydrostatic pressure gradient. In the rat lens, this [...] Read more.

In mice, the contraction of the ciliary muscle via the administration of pilocarpine reduces the zonular tension applied to the lens and activates the TRPV1-mediated arm of a dual feedback system that regulates the lens’ hydrostatic pressure gradient. In the rat lens, this pilocarpine-induced reduction in zonular tension also causes the water channel AQP5 to be removed from the membranes of fiber cells located in the anterior influx and equatorial efflux zones. Here, we determined whether this pilocarpine-induced membrane trafficking of AQP5 is also regulated by the activation of TRPV1. Using microelectrode-based methods to measure surface pressure, we found that pilocarpine also increased pressure in the rat lenses via the activation of TRPV1, while pilocarpine-induced removal of AQP5 from the membrane observed using immunolabelling was abolished by pre-incubation of the lenses with a TRPV1 inhibitor. In contrast, mimicking the actions of pilocarpine by blocking TRPV4 and then activating TRPV1 resulted in sustained increase in pressure and the removal of AQP5 from the anterior influx and equatorial efflux zones. These results show that the removal of AQP5 in response to a decrease in zonular tension is mediated by TRPV1 and suggest that regional changes to P_H2O contribute to lens hydrostatic pressure gradient regulation. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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14 pages, 3694 KiB

Open AccessArticle

AQP3-Dependent PI3K/Akt Modulation in Breast Cancer Cells

by Monika Mlinarić, Ivan Lučić, Lidija Milković, Inês V. da Silva, Ivana Tartaro Bujak, Vesna Musani, Graça Soveral and Ana Čipak Gašparović

Int. J. Mol. Sci. 2023, 24(9), 8133; https://doi.org/10.3390/ijms24098133 - 01 May 2023

Cited by 4 | Viewed by 2018

Abstract

Aquaporin 3 (AQP3) is a peroxiporin, a membrane protein that channels hydrogen peroxide in addition to water and glycerol. AQP3 expression also correlates with tumor progression and malignancy and is, therefore, a potential target in breast cancer therapy. In addition, epithelial growth factor [...] Read more.

Aquaporin 3 (AQP3) is a peroxiporin, a membrane protein that channels hydrogen peroxide in addition to water and glycerol. AQP3 expression also correlates with tumor progression and malignancy and is, therefore, a potential target in breast cancer therapy. In addition, epithelial growth factor receptor (EGFR) plays an important role in breast cancer. Therefore, we investigated whether disruption of the lipid raft harboring EGFR could affect AQP3 expression, and conversely, whether AQP3 silencing would affect the EGFR/phosphoinositide-3-kinase (PI3K)/Protein kinase B (PKB or Akt) signaling pathway in breast cancer cell lines with different malignant capacities. We evaluated H₂O₂ uptake, cell migratory capacity, and expression of PI3K, pAkt/Akt in three breast cancer cell lines, MCF7, SkBr3, and SUM159PT, and in the nontumorigenic breast epithelial cell line MCF10A. Our results show different responses between the tested cell lines, especially when compared to the nontumorigenic cell line. Neither lipid raft disruption nor EGF stimuli had an effect on PI3K/Akt pathway in MCF10A cell line. AQP3-silencing in SkBr3 and SUM159PT showed that AQP3 can modulate PI3K/Akt activation in these cells. Interestingly, SUM159PT cells increase nuclear factor-E2–related factor 2 (NRF2) in response to lipid raft disruption and EGF stimuli, suggesting an oxidative-dependent response to these treatments. These results suggest that in breast cancer cell lines, AQP3 is not directly related to PI3K/Akt pathway but rather in a cell-line-dependent manner. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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13 pages, 2342 KiB

Open AccessArticle

Genome-Engineered mpkCCDc14 Cells as a New Resource for Studying AQP2

by Hyo-Ju Jang, Hye-Jeong Park, Hong Seok Choi, Hyun Jun Jung and Tae-Hwan Kwon

Int. J. Mol. Sci. 2023, 24(2), 1684; https://doi.org/10.3390/ijms24021684 - 14 Jan 2023

Cited by 1 | Viewed by 1425

Abstract

mpkCCDc14 cells, a polarized epithelial cell line derived from mouse kidney cortical collecting ducts, are known to express the vasopressin V2 receptor (V2R) and aquaporin-2 (AQP2) that are responsive to vasopressin. However, a low abundance of the endogenous AQP2 protein in the absence [...] Read more.

mpkCCDc14 cells, a polarized epithelial cell line derived from mouse kidney cortical collecting ducts, are known to express the vasopressin V2 receptor (V2R) and aquaporin-2 (AQP2) that are responsive to vasopressin. However, a low abundance of the endogenous AQP2 protein in the absence of vasopressin and heterogeneity of AQP2 protein abundance among the cultured cells may limit the further application of the cell line in AQP2 studies. To overcome the limitation, we aimed to establish mpkCCDc14 cells constitutively expressing V2R and AQP2 via CRISPR/Cas9-mediated genome engineering technology (i.e., V2R-AQP2 cells). 3′- and 5′-Junction PCR revealed that the V2R-AQP2 expression cassette with a long insert size (~2.2 kb) was correctly integrated. Immunoblotting revealed the expression of products of integrated Aqp2 genes. Cell proliferation rate and dDAVP-induced cAMP production were not affected by the knock-in of Avpr2 and Aqp2 genes. The AQP2 protein abundance was significantly higher in V2R-AQP2 cells compared with control mpkCCDc14 cells in the absence of dDAVP and the integrated AQP2 was detected. Immunocytochemistry demonstrated that V2R-AQP2 cells exhibited more homogenous and prominent AQP2 labeling intensity in the absence of dDAVP stimulation. Moreover, prominent AQP2 immunolabeling (both AQP2 and pS256-AQP2) in the apical domain of the genome-edited cells was observed in response to dDAVP stimulation, similar to that in the unedited control mpkCCDc14 cells. Taken together, mpkCCDc14 cells constitutively expressing V2R and AQP2 via genome engineering could be exploited for AQP2 studies. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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24 pages, 7733 KiB

Open AccessArticle

TRPML1-Induced Lysosomal Ca²⁺ Signals Activate AQP2 Translocation and Water Flux in Renal Collecting Duct Cells

by Simona Ida Scorza, Serena Milano, Ilenia Saponara, Maira Certini, Roberta De Zio, Maria Grazia Mola, Giuseppe Procino, Monica Carmosino, Francesco Moccia, Maria Svelto and Andrea Gerbino

Int. J. Mol. Sci. 2023, 24(2), 1647; https://doi.org/10.3390/ijms24021647 - 13 Jan 2023

Cited by 5 | Viewed by 2191

Abstract

Lysosomes are acidic Ca²⁺ storage organelles that actively generate local Ca²⁺ signaling events to regulate a plethora of cell functions. Here, we characterized lysosomal Ca²⁺ signals in mouse renal collecting duct (CD) cells and we assessed their putative role in [...] Read more.

Lysosomes are acidic Ca²⁺ storage organelles that actively generate local Ca²⁺ signaling events to regulate a plethora of cell functions. Here, we characterized lysosomal Ca²⁺ signals in mouse renal collecting duct (CD) cells and we assessed their putative role in aquaporin 2 (AQP2)-dependent water reabsorption. Bafilomycin A1 and ML-SA1 triggered similar Ca²⁺ oscillations, in the absence of extracellular Ca²⁺, by alkalizing the acidic lysosomal pH or activating the lysosomal cation channel mucolipin 1 (TRPML1), respectively. TRPML1-dependent Ca²⁺ signals were blocked either pharmacologically or by lysosomes’ osmotic permeabilization, thus indicating these organelles as primary sources of Ca²⁺ release. Lysosome-induced Ca²⁺ oscillations were sustained by endoplasmic reticulum (ER) Ca²⁺ content, while bafilomycin A1 and ML-SA1 did not directly interfere with ER Ca²⁺ homeostasis per se. TRPML1 activation strongly increased AQP2 apical expression and depolymerized the actin cytoskeleton, thereby boosting water flux in response to an hypoosmotic stimulus. These effects were strictly dependent on the activation of the Ca²⁺/calcineurin pathway. Conversely, bafilomycin A1 led to perinuclear accumulation of AQP2 vesicles without affecting water permeability. Overall, lysosomal Ca²⁺ signaling events can be differently decoded to modulate Ca²⁺-dependent cellular functions related to the dock/fusion of AQP2-transporting vesicles in principal cells of the CD. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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24 pages, 38251 KiB

Open AccessArticle

Cortisol Interaction with Aquaporin-2 Modulates Its Water Permeability: Perspectives for Non-Genomic Effects of Corticosteroids

by Robin Mom, Stéphane Réty and Daniel Auguin

Int. J. Mol. Sci. 2023, 24(2), 1499; https://doi.org/10.3390/ijms24021499 - 12 Jan 2023

Cited by 4 | Viewed by 1375

Abstract

Aquaporins (AQPs) are water channels widely distributed in living organisms and involved in many pathophysiologies as well as in cell volume regulations (CVR). In the present study, based on the structural homology existing between mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs), cholesterol consensus motif [...] Read more.

Aquaporins (AQPs) are water channels widely distributed in living organisms and involved in many pathophysiologies as well as in cell volume regulations (CVR). In the present study, based on the structural homology existing between mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs), cholesterol consensus motif (CCM) and the extra-cellular vestibules of AQPs, we investigated the binding of corticosteroids on the AQP family through in silico molecular dynamics simulations of AQP2 interactions with cortisol. We propose, for the first time, a putative AQPs corticosteroid binding site (ACBS) and discussed its conservation through structural alignment. Corticosteroids can mediate non-genomic effects; nonetheless, the transduction pathways involved are still misunderstood. Moreover, a growing body of evidence is pointing toward the existence of a novel membrane receptor mediating part of these rapid corticosteroids’ effects. Our results suggest that the naturally produced glucocorticoid cortisol inhibits channel water permeability. Based on these results, we propose a detailed description of a putative underlying molecular mechanism. In this process, we also bring new insights on the regulatory function of AQPs extra-cellular loops and on the role of ions in tuning the water permeability. Altogether, this work brings new insights into the non-genomic effects of corticosteroids through the proposition of AQPs as the membrane receptor of this family of regulatory molecules. This original result is the starting point for future investigations to define more in-depth and in vivo the validity of this functional model. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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11 pages, 1120 KiB

Open AccessArticle

AQP5-1364A/C Polymorphism Affects AQP5 Promoter Methylation

by Katharina Rump, Theresa Spellenberg, Alexander von Busch, Alexander Wolf, Dominik Ziehe, Patrick Thon, Tim Rahmel, Michael Adamzik, Björn Koos and Matthias Unterberg

Int. J. Mol. Sci. 2022, 23(19), 11813; https://doi.org/10.3390/ijms231911813 - 05 Oct 2022

Cited by 4 | Viewed by 1245

Abstract

The quantity of aquaporin 5 protein in neutrophil granulocytes is associated with human sepsis-survival. The C-allele of the aquaporin (AQP5)-1364A/C polymorphism was shown to be associated with decreased AQP5 expression, which was shown to be relevant in this context leading towards [...] Read more.

The quantity of aquaporin 5 protein in neutrophil granulocytes is associated with human sepsis-survival. The C-allele of the aquaporin (AQP5)-1364A/C polymorphism was shown to be associated with decreased AQP5 expression, which was shown to be relevant in this context leading towards improved outcomes in sepsis. To date, the underlying mechanism of the C-allele—leading to lower AQP5 expression—has been unknown. Knowing the detailed mechanism depicts a crucial step with a target to further interventions. Genotype-dependent regulation of AQP5 expression might be mediated by the epigenetic mechanism of promoter methylation and treatment with epigenetic-drugs could maybe provide benefit. Hence, we tested the hypothesis that AQP5 promoter methylation differs between genotypes in specific types of immune cells.: AQP5 promoter methylation was quantified in cells of septic patients and controls by methylation-specific polymerase chain reaction and quantified by a standard curve. In cell-line models, AQP5 expression was analyzed after demethylation to determine the impact of promoter methylation on AQP5 expression. C-allele of AQP5-1364 A/C promoter polymorphism is associated with a five-fold increased promoter methylation in neutrophils (p = 0.0055) and a four-fold increase in monocytes (p = 0.0005) and lymphocytes (p = 0.0184) in septic patients and healthy controls as well. In addition, a decreased AQP5 promoter methylation was accompanied by an increased AQP5 expression in HL-60 (p = 0.0102) and REH cells (p = 0.0102). The C-allele which is associated with lower gene expression in sepsis is accompanied by a higher methylation level of the AQP5 promoter. Hence, AQP5 promoter methylation could depict a key mechanism in genotype-dependent expression. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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Review

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15 pages, 766 KiB

Open AccessReview

Male Sex Hormones, Metabolic Syndrome, and Aquaporins: A Triad of Players in Male (in)Fertility

by Diana C. Nunes, João C. Ribeiro, Marco G. Alves, Pedro F. Oliveira and Raquel L. Bernardino

Int. J. Mol. Sci. 2023, 24(3), 1960; https://doi.org/10.3390/ijms24031960 - 19 Jan 2023

Viewed by 2958

Abstract

Infertility is becoming a chronic and emerging problem in the world. There is a resistant stigma that this health condition is mostly due to the female, although the literature supports that the responsibility for the onset of infertility is equally shared between both [...] Read more.

Infertility is becoming a chronic and emerging problem in the world. There is a resistant stigma that this health condition is mostly due to the female, although the literature supports that the responsibility for the onset of infertility is equally shared between both sexes in more or less equal proportions. Nevertheless, male sex hormones, particularly testosterone (T), are key players in male-related infertility. Indeed, hypogonadism, which is also characterized by changes in T levels, is one of the most common causes of male infertility and its incidence has been interconnected to the increased prevalence of metabolic diseases. Recent data also highlight the role of aquaporin (AQP)-mediated water and solute diffusion and the metabolic homeostasis in testicular cells suggesting a strong correlation between AQPs function, metabolism of testicular cells, and infertility. Indeed, recent studies showed that both metabolic and sexual hormone concentrations can change the expression pattern and function of AQPs. Herein, we review up-to-date information on the involvement of AQP-mediated function and permeability in men with metabolic syndrome and testosterone deficit, highlighting the putative mechanisms that show an interaction between sex hormones, AQPs, and metabolic syndrome that may contribute to male infertility. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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25 pages, 2014 KiB

Open AccessReview

Aquaporin-5 Dynamic Regulation

by Claudia D’Agostino, Dorian Parisis, Clara Chivasso, Maryam Hajiabbas, Muhammad Shahnawaz Soyfoo and Christine Delporte

Int. J. Mol. Sci. 2023, 24(3), 1889; https://doi.org/10.3390/ijms24031889 - 18 Jan 2023

Cited by 8 | Viewed by 2514

Abstract

Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and the movement of hydrogen peroxide and CO₂. Various mechanisms have been shown to dynamically regulate AQP5 expression, trafficking, and function. [...] Read more.

Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and the movement of hydrogen peroxide and CO₂. Various mechanisms have been shown to dynamically regulate AQP5 expression, trafficking, and function. Besides fulfilling its primary water permeability function, AQP5 has been shown to regulate downstream effectors playing roles in various cellular processes. This review provides a comprehensive overview of the current knowledge of the upstream and downstream effectors of AQP5 to gain an in-depth understanding of the physiological and pathophysiological processes involving AQP5. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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10 pages, 1342 KiB

Open AccessReview

Physiological Cooperation between Aquaporin 5 and TRPV4

by Kata Kira Kemény and Eszter Ducza

Int. J. Mol. Sci. 2022, 23(19), 11634; https://doi.org/10.3390/ijms231911634 - 01 Oct 2022

Cited by 2 | Viewed by 1759

Abstract

Aquaporins—among them, AQP5—are responsible for transporting water across biological membranes, which is an important process in all living organisms. The transient receptor potential channel 4 (TRPV4) is a cation channel that is mostly calcium-permeable and can also be activated by osmotic stimuli. It [...] Read more.

Aquaporins—among them, AQP5—are responsible for transporting water across biological membranes, which is an important process in all living organisms. The transient receptor potential channel 4 (TRPV4) is a cation channel that is mostly calcium-permeable and can also be activated by osmotic stimuli. It plays a role in a number of different functions in the body, e.g., the development of bones and cartilage, and it is involved in the body’s osmoregulation, the generation of certain types of sensation (pain), and apoptosis. Our earlier studies on the uterus and the literature data aroused our interest in the physiological role of the cooperation of AQP5 and TRPV4. In this review, we focus on the co-expression and cooperation of AQP5 and TRPV4 in the lung, salivary glands, uterus, adipose tissues, and lens. Understanding the cooperation between AQP5 and TRPV4 may contribute to the development of new drug candidates and the therapy of several disorders (e.g., preterm birth, cataract, ischemia/reperfusion-induced edema, exercise- or cold-induced asthma). Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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