International Journal of Molecular Sciences

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11 pages, 1508 KiB

Open AccessArticle

Bumetanide-Derived Aquaporin 1 Inhibitors, AqB013 and AqB050 Inhibit Tube Formation of Endothelial Cells through Induction of Apoptosis and Impaired Migration In Vitro

by Yoko Tomita, Helen M. Palethorpe, Eric Smith, Maryam Nakhjavani, Amanda R. Townsend, Timothy J. Price, Andrea J. Yool and Jennifer E. Hardingham

Int. J. Mol. Sci. 2019, 20(8), 1818; https://doi.org/10.3390/ijms20081818 - 12 Apr 2019

Cited by 18 | Viewed by 4196

Abstract

AqB013 and AqB050 compounds inhibit aquaporin 1 (AQP1), a dual water and ion channel implicated in tumour angiogenesis. We tested AqB013 and AqB050 either as monotherapy or in combination on tube formation of murine endothelial cells (2H-11 and 3B-11) and human umbilical vascular [...] Read more.

AqB013 and AqB050 compounds inhibit aquaporin 1 (AQP1), a dual water and ion channel implicated in tumour angiogenesis. We tested AqB013 and AqB050 either as monotherapy or in combination on tube formation of murine endothelial cells (2H-11 and 3B-11) and human umbilical vascular endothelial cells (HUVECs). The mechanism underlying their anti-tubulogenic effect was explored by examining cell viability, induction of apoptosis and migration using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, Annexin V/propidium iodide apoptosis assay and scratch wound assay. Tube formation of all the cell lines was inhibited by AqB013, AqB050 and the combination of the two compounds. The inhibition of 2H-11 and 3B-11 was frequently accompanied by impaired migration, whereas that of HUVEC treated with AqB050 and the combination was associated with reduced cell viability due to apoptosis. AqB013 and AqB050 exhibited an anti-tubulogenic effect through inhibition of AQP1-mediated cell migration and induction of apoptosis. Together with previously reported anti-tumour cell effect of AqB013 and AqB050, our findings support further evaluation of these compounds as potential cancer therapeutics. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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15 pages, 1842 KiB

Open AccessArticle

Changes in the Expression of Aquaporin-3 in the Gastrointestinal Tract Affect Drug Absorption

by Nobutomo Ikarashi, Chika Nagoya, Risako Kon, Satoshi Kitaoka, Sayuri Kajiwara, Masayo Saito, Akane Kawabata, Wataru Ochiai and Kiyoshi Sugiyama

Int. J. Mol. Sci. 2019, 20(7), 1559; https://doi.org/10.3390/ijms20071559 - 28 Mar 2019

Cited by 7 | Viewed by 3847

Abstract

Aquaporin-3 (AQP3) plays an important role in water transport in the gastrointestinal (GI) tract. In this study, we conducted a Caco-2 cell permeability assay to examine how changes in the expression and function of AQP3 affect the rate at which a drug is [...] Read more.

Aquaporin-3 (AQP3) plays an important role in water transport in the gastrointestinal (GI) tract. In this study, we conducted a Caco-2 cell permeability assay to examine how changes in the expression and function of AQP3 affect the rate at which a drug is absorbed via passive transport in the GI tract. When the function of AQP3 was inhibited by mercuric chloride or phloretin, there was no change in warfarin permeability. In contrast, when the expression of AQP3 protein was decreased by prostaglandin E₂ (PGE₂) treatment, warfarin permeability increased to approximately twice the control level, and membrane fluidity increased by 15%. In addition, warfarin permeability increased to an extent comparable to that after PGE₂ treatment when cell membrane fluidity was increased by 10% via boric acid/EDTA treatment. These findings suggest the possibility that the increased drug absorption under decreased AQP3 expression was attributable to increased membrane fluidity. The results of this study demonstrate that the rate of water transport has little effect on drug absorption. However, our findings also indicate that although AQP3 and other similar transmembrane proteins do not themselves transport drugs, changes in their expression levels can cause changes in cell membrane fluidity, thus affecting drug absorption rates. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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11 pages, 3656 KiB

Open AccessArticle

Covalently Linking Oligomerization-Impaired GlpF Protomers Does Not Completely Re-establish Wild-Type Channel Activity

by Noreen Klein, Margareta Trefz and Dirk Schneider

Int. J. Mol. Sci. 2019, 20(4), 927; https://doi.org/10.3390/ijms20040927 - 20 Feb 2019

Cited by 3 | Viewed by 3264

Abstract

Integral membrane proteins of the aquaporin family facilitate rapid water flux across cellular membranes in all domains of life. Although the water-conducting pore is clearly defined in an aquaporin monomer, all aquaporins assemble into stable tetramers. In order to investigate the role of [...] Read more.

Integral membrane proteins of the aquaporin family facilitate rapid water flux across cellular membranes in all domains of life. Although the water-conducting pore is clearly defined in an aquaporin monomer, all aquaporins assemble into stable tetramers. In order to investigate the role of protomer–protomer interactions, we analyzed the activity of heterotetramers containing increasing fractions of mutated monomers, which have an impaired oligomerization propensity and activity. In order to enforce interaction between the protomers, we designed and analyzed a genetically fused homotetramer of GlpF, the aquaglyceroporin of the bacterium Escherichia coli (E. coli). However, increasing fractions of the oligomerization-impaired mutant GlpF E43A affected the activity of the GlpF heterotetramer in a nearly linear manner, indicating that the reduced protein activity, caused by the introduced mutations, cannot be fully compensated by simply covalently linking the monomers. Taken together, the results underline the importance of exactly positioned monomer–monomer contacts in an assembled GlpF tetramer. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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18 pages, 4091 KiB

Open AccessArticle

Maternal Protein Restriction Differentially Alters the Expression of AQP1, AQP9 and VEGFr-2 in the Epididymis of Rat Offspring

by Marilia Martins Cavariani, Talita de Mello Santos, Dhrielly Natalia Pereira, Luiz Gustavo de Almeida Chuffa, Patricia Fernanda Felipe Pinheiro, Wellerson Rodrigo Scarano and Raquel Fantin Domeniconi

Int. J. Mol. Sci. 2019, 20(3), 469; https://doi.org/10.3390/ijms20030469 - 22 Jan 2019

Cited by 9 | Viewed by 3488

Abstract

Background: Maternal protein restriction causes sperm alterations in the offspring, most of which are associated with epididymal functions. Because fluid reabsorption/secretion dynamics in the epididymal environment play important roles in the process of sperm maturation and concentration, we investigated the effects of maternal [...] Read more.

Background: Maternal protein restriction causes sperm alterations in the offspring, most of which are associated with epididymal functions. Because fluid reabsorption/secretion dynamics in the epididymal environment play important roles in the process of sperm maturation and concentration, we investigated the effects of maternal protein restriction on the expression of aquaporins (AQP1 and AQP9), vascular endothelial growth factor (VEGFa), and its receptor VEGFr-2 in different stages of postnatal epididymal development. Methods: Pregnant rats were divided into groups that received normoprotein (17% protein) and low-protein diets (6% protein) during gestation and lactation. After weaning, male rats only received the standard diet and were euthanized at the predetermined ages of 21, 44 and 120 days. Results: Maternal protein restriction decreased AQP1 and AQP9 expression in the initial segment and caput epididymis compared to the increased expression of these proteins observed in the corpus and cauda at all ages. Although protein restriction reduced the microvasculature density (MVD) on postnatal day (PND) 21 and 44, the MVD was unaltered on PND 120. Conclusions: Maternal protein restriction changed the structure or function of the offspring’s epididymis, specifically by affecting fluid dynamics and vasculogenesis in important stages of epididymis development. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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16 pages, 3661 KiB

Open AccessArticle

Aquaporins Alteration Profiles Revealed Different Actions of Senna, Sennosides, and Sennoside A in Diarrhea-Rats

by Yixin Cao, Ying He, Cong Wei, Jing Li, Lejing Qu, Huiqin Zhang, Ying Cheng and Boling Qiao

Int. J. Mol. Sci. 2018, 19(10), 3210; https://doi.org/10.3390/ijms19103210 - 17 Oct 2018

Cited by 28 | Viewed by 4812

Abstract

Senna and its main components sennosides are well-known effective laxative drugs and are used in the treatment of intestinal constipation in the world. Their potential side effects have attracted more attention in clinics but have little scientific justification. In this study, senna extract [...] Read more.

Senna and its main components sennosides are well-known effective laxative drugs and are used in the treatment of intestinal constipation in the world. Their potential side effects have attracted more attention in clinics but have little scientific justification. In this study, senna extract (SE), sennosides (SS), and sennoside A (SA) were prepared and used to generate diarrhea rats. The diarrhea rats were investigated with behaviors, clinical signs, organ index, pathological examination, and gene expression on multiple aquaporins (Aqps) including Aqp1, Aqp2, Aqp3, Aqp4, Aqp5, Aqp6, Aqp7, Aqp8, Aqp9, and Aqp11. Using qRT-PCR, the Aqp expression profiles were constructed for six organs including colon, kidney, liver, spleen, lung, and stomach. The Aqp alteration profiles were characterized and was performed with Principle Component Analysis (PCA). The SE treatments on the rats resulted in a significant body weight loss (p < 0.001), significant increases (p < 0.001) on the kidney index (27.72%) and liver index (42.55%), and distinguished changes with up-regulation on Aqps expressions in the kidneys and livers. The SS treatments showed prominent laxative actions and down regulation on Aqps expression in the colons. The study results indicated that the SE had more influence/toxicity on the kidneys and livers. The SS showed more powerful actions on the colons. We suggest that the caution should be particularly exercised in the patients with kidney and liver diseases when chronic using senna-based products. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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Review

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20 pages, 758 KiB

Open AccessReview

Aquaporin Channels in the Heart—Physiology and Pathophysiology

by Arie O. Verkerk, Elisabeth M. Lodder and Ronald Wilders

Int. J. Mol. Sci. 2019, 20(8), 2039; https://doi.org/10.3390/ijms20082039 - 25 Apr 2019

Cited by 32 | Viewed by 6415

Abstract

Mammalian aquaporins (AQPs) are transmembrane channels expressed in a large variety of cells and tissues throughout the body. They are known as water channels, but they also facilitate the transport of small solutes, gasses, and monovalent cations. To date, 13 different AQPs, encoded [...] Read more.

Mammalian aquaporins (AQPs) are transmembrane channels expressed in a large variety of cells and tissues throughout the body. They are known as water channels, but they also facilitate the transport of small solutes, gasses, and monovalent cations. To date, 13 different AQPs, encoded by the genes AQP0–AQP12, have been identified in mammals, which regulate various important biological functions in kidney, brain, lung, digestive system, eye, and skin. Consequently, dysfunction of AQPs is involved in a wide variety of disorders. AQPs are also present in the heart, even with a specific distribution pattern in cardiomyocytes, but whether their presence is essential for proper (electro)physiological cardiac function has not intensively been studied. This review summarizes recent findings and highlights the involvement of AQPs in normal and pathological cardiac function. We conclude that AQPs are at least implicated in proper cardiac water homeostasis and energy balance as well as heart failure and arsenic cardiotoxicity. However, this review also demonstrates that many effects of cardiac AQPs, especially on excitation-contraction coupling processes, are virtually unexplored. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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22 pages, 3434 KiB

Open AccessReview

Inhibitors of Mammalian Aquaporin Water Channels

by Mohammed Abir-Awan, Philip Kitchen, Mootaz M. Salman, Matthew T. Conner, Alex C. Conner and Roslyn M. Bill

Int. J. Mol. Sci. 2019, 20(7), 1589; https://doi.org/10.3390/ijms20071589 - 29 Mar 2019

Cited by 100 | Viewed by 9860

Abstract

Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and [...] Read more.

Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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15 pages, 249 KiB

Open AccessReview

Peroxiporins in Cancer

by Cecilia Prata, Silvana Hrelia and Diana Fiorentini

Int. J. Mol. Sci. 2019, 20(6), 1371; https://doi.org/10.3390/ijms20061371 - 19 Mar 2019

Cited by 42 | Viewed by 4339

Abstract

The transport of H₂O₂ across membranes by specific aquaporins (AQPs) has been considered the last milestone in the timeline of hydrogen peroxide discoveries in biochemistry. According to its concentration and localization, H₂O₂ can be dangerous or acts [...] Read more.

The transport of H₂O₂ across membranes by specific aquaporins (AQPs) has been considered the last milestone in the timeline of hydrogen peroxide discoveries in biochemistry. According to its concentration and localization, H₂O₂ can be dangerous or acts as a signaling molecule in various cellular processes as either a paracrine (intercellular) and/or an autocrine (intracellular) signal. In this review, we investigate and critically examine the available information on AQP isoforms able to facilitate H₂O₂ across biological membranes (“peroxiporins”), focusing in particular on their role in cancer. Moreover, the ability of natural compounds to modulate expression and/or activity of peroxiporins is schematically reported and discussed. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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16 pages, 4144 KiB

Open AccessReview

Aquaporins in Renal Diseases

by Jinzhao He and Baoxue Yang

Int. J. Mol. Sci. 2019, 20(2), 366; https://doi.org/10.3390/ijms20020366 - 16 Jan 2019

Cited by 74 | Viewed by 15064

Abstract

Aquaporins (AQPs) are a family of highly selective transmembrane channels that mainly transport water across the cell and some facilitate low-molecular-weight solutes. Eight AQPs, including AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11, are expressed in different segments and various cells in [...] Read more.

Aquaporins (AQPs) are a family of highly selective transmembrane channels that mainly transport water across the cell and some facilitate low-molecular-weight solutes. Eight AQPs, including AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11, are expressed in different segments and various cells in the kidney to maintain normal urine concentration function. AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation. Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus. Studies with animal models show AQPs are related to acute kidney injury and various chronic kidney diseases, such as diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma. Experimental data suggest ideal prospects for AQPs as biomarkers and therapeutic targets in clinic. This review article mainly focuses on recent advances in studying AQPs in renal diseases. Full article

(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms 2.0)

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