| 1. |
- Huber, Vincent J., et al.
(författare)
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Aquaporins : Chemical inhibition by small molecules
- 2016
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Ingår i: Aquaporins in Health and Disease : New Molecular Targets for Drug Discovery - New Molecular Targets for Drug Discovery. - 9781498707831 - 9781498707848 ; , s. 249-271
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Bokkapitel (refereegranskat)abstract
- The human genome encodes 13 aquaporin isoforms with characteristic substrate specificity that are expressed at specific locations throughout the body. Of these isoforms, AQPs 1-4 serve important functions in renal water reabsorption. Consequently, specific AQP inhibitors have been proposed as 'aquaretics', a new class of drugs suitable to induce diuresis without concomitant salt wasting. Furthermore, animal experiments suggested that AQP4 inhibitors could be useful to treat some forms of brain edema. Other proposed applications for AQP inhibitors involve amongst others treatment of diabetes, inflammatory skin diseases and cancer. However, few of these putative applications have been critically evaluated against current forms of therapy. Furthermore, development of AQP inhibitors remains difficult and despite numerous efforts during at least the last 15 years very few AQP inhibitors have been described. Moreover, none of the hitherto described substances have been developed to a level where meaningful verification of proposed AQP drug targets in preclinical or clinical settings was possible. Nonetheless, encouraging progress towards development of such substances has been made during recent years. Novel cell-based assays facilitate high throughput screening of chemical compound libraries for hit discovery. AQP 3D structures have been solved for 10 isoforms, which can support rapidly evolving computational hit discovery methods, as well as hit to lead programs. In this chapter, we will provide a critical review of current evidence supporting relevance of AQPs as drug targets, describe current methods for AQP inhibitor discovery and will try to highlight challenges that remain before successful AQP inhibitor development.
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| 2. |
- Lindskog, Cecilia, et al.
(författare)
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A Systematic Characterization of Aquaporin-9 Expression in Human Normal and Pathological Tissues
- 2016
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Ingår i: Journal of Histochemistry and Cytochemistry. - : SAGE Publications. - 0022-1554 .- 1551-5044. ; 64:5, s. 287-300
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Tidskriftsartikel (refereegranskat)abstract
- AQP9 is known to facilitate hepatocyte glycerol uptake. Murine AQP9 protein expression has been verified in liver, skin, epididymis, epidermis and neuronal cells using knockout mice. Further expression sites have been reported in humans. We aimed to verify AQP9 expression in a large set of human normal organs, different cancer types, rheumatoid arthritis synovial biopsies as well as in cell lines and primary cells. Combining standardized immunohistochemistry with high-throughput mRNA sequencing, we found that AQP9 expression in normal tissues was limited, with high membranous expression only in hepatocytes. In cancer tissues, AQP9 expression was mainly found in hepatocellular carcinomas, suggesting no general contribution of AQP9 to carcinogenesis. AQP9 expression in a subset of rheumatoid arthritis synovial tissue samples was affected by Humira, thereby supporting a suggested role of TNF alpha in AQP9 regulation in this disease. Among cell lines and primary cells, LP-1 myeloma cells expressed high levels of AQP9, whereas low expression was observed in a few other lymphoid cell lines. AQP9 mRNA and protein expression was absent in HepG2 hepatocellular carcinoma cells. Overall, AQP9 expression in human tissues appears to be more selective than in mice.
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| 3. |
- Sonntag, Yonathan, et al.
(författare)
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Identification and characterization of potent and selective aquaporin-3 and aquaporin-7 inhibitors
- 2019
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 294:18, s. 7377-7387
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Tidskriftsartikel (refereegranskat)abstract
- The aquaglyceroporins are a subfamily of aquaporins that conduct both water and glycerol. Aquaporin-3 (AQP3) has an important physiological function in renal water reabsorption, and AQP3-mediated hydrogen peroxide (H2O2) permeability can enhance cytokine signaling in several cell types. The related aquaglyceroporin AQP7 is required for dendritic cell chemokine responses and antigen uptake. Selective small-molecule inhibitors are desirable tools for investigating the biological and pathological roles of these and other AQP isoforms. Here, using a calcein fluorescence quenching assay we screened a library of 7360 drug-like small molecules for inhibition of mouse AQP3 water permeability. Hit confirmation and expansion with commercially available substances identified the ortho-chloride-containing compound DFP00173, which inhibited mouse and human AQP3 with an IC50 of ~0.1-0.4 μM but had low efficacy toward mouse AQPs 7 and 9. Surprisingly, inhibitor specificity testing revealed that the methylurea-linked compound Z433927330, a partial AQP3 inhibitor (IC50 ~0.7-0.9 μM), is a potent and efficacious inhibitor of mouse AQP7 water permeability (IC50 ~0.2 μM). Stopped-flow light-scattering measurements confirmed that DFP00173 and Z433927330 inhibit AQP3 glycerol permeability in human erythrocytes. Moreover, DFP00173, Z433927330, and the previously identified AQP9 inhibitor RF03176 blocked aquaglyceroporin H2O2 permeability. Molecular docking to AQP3, AQP7, and AQP9 homology models suggested interactions between these inhibitors and aquaglyceroporins at similar binding sites. DFP00173 and Z433927330 constitute selective and potent AQP3 and AQP7 inhibitors, respectively, and contribute to a set of isoform-specific aquaglyceroporin inhibitors that will facilitate the evaluation of these AQP isoforms as drug targets.
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| 4. |
- Spégel, Peter, et al.
(författare)
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Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice.
- 2015
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor-deficient (db/db) obese mice on a C57BL/6 × C57BLKS mixed genetic background. Furthermore, shRNA-mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet-induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9(wt) db/db and Aqp9(-/-) db/db mice did not differ in body weight and liver TAG contents. On the C57BL/6 genetic background, we observed elevated plasma glucose in Aqp9(-/-) db/db mice (+1.1 mmol/L, life-time average), while plasma insulin concentration was reduced at the time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9(wt) db/db and Aqp9(-/-) db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%) and glucose (+24%), and reduction in threonate (all at q < 0.1) in Aqp9(-/-) db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP9 in glycerol metabolism of obese C57BL/6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis.
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