Journal articles: 'Aquaporin 1 inhibitors'

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Esteva-Font, Cristina, Byung-Ju Jin, Sujin Lee, Puay-Wah Phuan, Marc O. Anderson, and A. S. Verkman. "Experimental Evaluation of Proposed Small-Molecule Inhibitors of Water Channel Aquaporin-1." Molecular Pharmacology 89, no. 6 (March 18, 2016): 686–93. http://dx.doi.org/10.1124/mol.116.103929.

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Patil, Rajkumar V., Shouxi Xu, Alfred N. van Hoek, Andrew Rusinko, Zixia Feng, Jesse May, Mark Hellberg, et al. "Rapid Identification of Novel Inhibitors of the Human Aquaporin-1 Water Channel." Chemical Biology & Drug Design 87, no. 5 (January 17, 2016): 794–805. http://dx.doi.org/10.1111/cbdd.12713.

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Yamaguchi, Takeo, Yohei Iwata, Shingo Miura, Yukari Maehara, and Kazuyuki Nozawa. "Enhancement of Pressure-Induced Hemolysis by Aquaporin-1 Inhibitors in Human Erythrocytes." Bulletin of the Chemical Society of Japan 85, no. 4 (April 15, 2012): 497–503. http://dx.doi.org/10.1246/bcsj.20110285.

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Ruiz Carrillo, David, Janet To Yiu Ying, Dina Darwis, Cin Huang Soon, Tobias Cornvik, Jaume Torres, and Julien Lescar. "Crystallization and preliminary crystallographic analysis of human aquaporin 1 at a resolution of 3.28 Å." Acta Crystallographica Section F Structural Biology Communications 70, no. 12 (November 14, 2014): 1657–63. http://dx.doi.org/10.1107/s2053230x14024558.

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Aquaporin water channels (AQPs) are found in almost every organism from humans to bacteria. In humans, 13 classes of AQPs control water and glycerol homeostasis. Knockout studies have suggested that modulating the activity of AQPs could be beneficial for the treatment of several pathologies. In particular, aquaporin 1 is a key factor in cell migration and angiogenesis, and constitutes a possible target for anticancer compounds and also for the treatment of glaucoma. Here, a preliminary crystallographic analysis at 3.28 Å resolution of crystals of human aquaporin 1 (hAQP1) obtained from protein expressed in Sf9 insect cells is reported. The crystals belonged to the tetragonal space groupI422, with unit-cell parametersa=b= 89.28,c= 174.9 Å, and contained one monomer per asymmetric unit. The hAQP1 biological tetramer is generatedviathe crystallographic fourfold axis. This work extends previous electron crystallographic studies that used material extracted from human red blood cells, in which the resolution was limited to approximately 3.8 Å. It will inform efforts to improve lattice contacts and the diffraction limit for the future structure-based discovery of specific hAQP1 inhibitors.

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Bauer, Georg. "Inhibition of Membrane-Associated Catalase, Extracellular ROS/RNS Signaling and Aquaporin/H2O2-Mediated Intracellular Glutathione Depletion Cooperate during Apoptosis Induction in the Human Gastric Carcinoma Cell Line MKN-45." Antioxidants 10, no. 10 (October 9, 2021): 1585. http://dx.doi.org/10.3390/antiox10101585.

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The human gastric carcinoma cell line MKN-45 is a prototype of bona fide tumor cells, as it is protected from the NADPH oxidase-1 (NOX-1)-driven HOCl- and nitric oxide (NO)/peroxynitrite apoptosis-inducing signaling pathways by a membrane-associated catalase. The use of inhibitors/scavengers shows that inhibition of membrane-associated catalase is sufficient for the activation of NO/peroxynitrite or HOCl signaling. However, this signaling is not sufficient for apoptosis induction, as intracellular glutathione peroxidase/glutathione counteracts these signaling effects. Therefore, intrusion of extracellular tumor cell-derived H2O2 through aquaporins is required for the full apoptosis-inducing effect of extracellular reactive oxygen/nitrogen species. This secondary step in apoptosis induction can be prevented by inhibition of aquaporins, inhibition of NOX1 and decomposition of H2O2. Pretreatment with inhibitors of glutathione synthase or the cysteine-glutamine antiporter (xC transporter) abrogate the requirement for aquaporin/H2O2-mediated glutathione depletion, thus demonstrating that intracellular glutathione is the target of intruding H2O2. These data allow definition of mechanistic interactions between ROS/RNS signaling after inhibition of membrane-associated catalase, the sensitizing effects of aquaporins/H2O2 and the counteraction of the xC transporter/glutathione synthase system. Knowledge of these mechanistic interactions is required for the understanding of selective apoptosis induction in tumor cells through reestablishment of apoptosis-inducing ROS/RNS signaling.

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Schnitzer, J. E., and P. Oh. "Aquaporin-1 in plasma membrane and caveolae provides mercury-sensitive water channels across lung endothelium." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 1 (January 1, 1996): H416—H422. http://dx.doi.org/10.1152/ajpheart.1996.270.1.h416.

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Classically, water transport across endothelium of the continuous type found in the microvessels of many organs such as lung was thought to occur almost completely via the paracellular pathway through intercellular junctions. Direct transmembrane and transcellular transport was considered to be minimal. In this study, we focused on the critical transport interface in direct contact with the circulating blood by purifying luminal endothelial cell plasma membranes directly from rat lungs and then isolating the noncoated plasmalemmal vesicles or caveolae from these membranes. Immunoblotting of these fractions showed that the transmembrane water channel protein aquaporin-1 was amply expressed on the endothelial cell surface at levels comparable to rat erythrocyte plasma membranes. It was found concentrated, but not exclusively, in caveolae. The functional role of these water channels in transport was examined in rat lungs perfused in situ with tritiated water by testing known inhibitors of aquaporin-1-mediated transmembrane water transport. Mercurial sulfhydryl reagents such as HgCl2 reversibly reduced tritiated water uptake without affecting small solute transport. Just like certain epithelia, endothelia might express physiologically relevant amounts of aquaporin-1 on their cell surface to permit direct, mercurial-sensitive, transcellular transport of water.

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Yang, Baoxue, Jung Kyung Kim, and A. S. Verkman. "Comparative efficacy of HgCl2with candidate aquaporin-1 inhibitors DMSO, gold, TEA+and acetazolamide." FEBS Letters 580, no. 28-29 (November 20, 2006): 6679–84. http://dx.doi.org/10.1016/j.febslet.2006.11.025.

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Lee, Wing-Kee, Ulrich Bork, Fatemeh Gholamrezaei, and Frank Thévenod. "Cd2+-induced cytochrome c release in apoptotic proximal tubule cells: role of mitochondrial permeability transition pore and Ca2+ uniporter." American Journal of Physiology-Renal Physiology 288, no. 1 (January 2005): F27—F39. http://dx.doi.org/10.1152/ajprenal.00224.2004.

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Cd2+ induces apoptosis of kidney proximal tubule (PT) cells. Mitochondria play a pivotal role in toxic compound-induced apoptosis by releasing cytochrome c. Our objective was to investigate the mechanisms underlying Cd2+-induced cytochrome c release from mitochondria in rat PT cells. Using Hoechst 33342 or MTT assay, 10 μM Cd2+ induced ∼5–10% apoptosis in PT cells at 6 and 24 h, which was associated with cytochrome c and apoptosis-inducing factor release at 24 h only. This correlated with previously described maximal intracellular Cd2+ concentrations at 24 h, suggesting that elevated Cd2+ may directly induce mitochondrial liberation of proapoptotic factors. Indeed, Cd2+ caused swelling of energized isolated kidney cortex mitochondria (EC50 ∼9 μM) and cytochrome c release, which were independent of permeability transition pore (PTP) opening since PTP inhibitors cyclosporin A or bongkrekic acid had no effect. On the contrary, Cd2+ inhibited swelling and cytochrome c release induced by PTP openers (PO43− or H2O2+Ca2+). The mitochondrial Ca2+ uniporter (MCU) played a key role in mitochondrial damage: 1) MCU inhibitors (La3+, ruthenium red, Ru360) prevented swelling and cytochrome c release; and 2) ruthenium red attenuated Cd2+ inhibition of PO43−-induced swelling. Using the Cd2+-sensitive fluorescent indicator FluoZin-1, Cd2+ was also taken up by mitoplasts. The aquaporin inhibitor AgNO3 abolished Cd2+-induced swelling of mitoplasts. This could be partially mediated by activation of the mitoplast-enriched water channel aquaporin-8. Thus cytosolic Cd2+ concentrations exceeding a certain threshold may directly cause mitochondrial damage and apoptotic development by interacting with MCU and water channels in the inner mitochondrial membrane.

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Chen, Gang, Chenjuan Yao, Takahiro Hasegawa, Tetsuya Akamatsu, Hiroshi Yoshimura, and Kazuo Hosoi. "Effects of isoproterenol on aquaporin 5 levels in the parotid gland of mice in vivo." American Journal of Physiology-Endocrinology and Metabolism 306, no. 1 (January 1, 2014): E100—E108. http://dx.doi.org/10.1152/ajpendo.00317.2013.

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In the membrane fraction of mouse parotid gland (PG), the protein level of aquaporin 5 (AQP5), a member of the water channel family, was increased by injection (ip) of isoproterenol (IPR), a β-adrenergic agonist, at 1 h, and stayed at high levels until 6 h; this change occurred simultaneously as amylase secretion. The AQP5 level then decreased and returned toward the original level at 12–48 h. After IPR injection, the AQP5 mRNA gradually increased and reached a maximum at 24 h. The facts suggest a rapid appearance of AQP5 at plasma membrane by IPR and subsequent degradation/metabolism by activation of proteolytic systems. Pretreatment of animals with two calpain inhibitors, N-Ac-Leu-Leu-methininal (ALLM) and calpeptin, as well as a protein synthesis inhibitor, cycloheximide (CHX), significantly suppressed the IPR-induced AQP5 degradation in the PG membrane fraction; such suppression was not observed by two proteasome inhibitors, MG132 and lactacystin, or the lysosome denaturant chloroquine, although most of these inhibitors increased AQP5 protein levels in unstimulated mice. The AQP5 protein was also degraded by μ-calpain in vitro. Furthermore, we demonstrated that μ-calpain was colocalized with AQP5 in the acinar cells by immunohistochemistry, and its activity in the PG was increased at 6 h after IPR injection. These results suggest that the calpain system was responsible for IPR-induced AQP5 degradation in the parotid gland and that such a system was coupled to the secretory-restoration cycle of amylase in the PG.

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Rammos, G., A. Panutsopoulos, K. Xynos, E. Koufogeorga, V. Peppes, K. Kostopoulos, and P. Turli. "Hyponatremia and Selective Serotonin Reuptake Inhibitors." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70746-1.

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Aims:Hyponatremia (HPN) is a potentially lethal electrolytic disturbance. Certain medical treatments are integrated in the etiology of that sodium disorder. We retrospectively studied the rate of HPN in patients examined in the emergency room (ER) of Alexandra Hospital receiving a selective serotonin reuptake inhibitor (SSRI).Methods:17,410 patients, 55.54% women and 44.46% men were examined in the ER over a one year period. 281 patients (1,61% of total) presented with HPN, 162 were women (57.6%) and 121 (42.3%) men. Plasma Sodium values ≤ 133mEq/l defined HPN. 13 of the 281 patients with HPN (4.6%) with no renal, heart or hepatic impairment were on an SSRI regimen.Results:11 of 162 women (6.8%) presented with HPN were receiving concurrently SSRI and either thiazide diuretic (3 ) or furosemide (2 ). 2 of 121 men (1.65%) were on SSRI regimen and furosemide. SSRI dosage was in all cases within suggested therapeutic limits. Table 1 demonstrates mean values and standard deviation of all the parameters examined.PatientsAgePlasma Na+Plasma K+Plasma CreatininePlasma UreaHct1366,9 +/- 17,4 years127,2 +/- 6,1 mEq/4 +/- 0,7 mEq/l1.06 +/-0,5 mg%39,8 +/- 16,2 mg%36,7 +/ 2,9%Conclusion:SSRI therapy presents a potential cause for HPN principally in women older than 65 years old with increasing risk when diuretic is used concomitantly. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and expression conversion of aquaporin-2 receptors of the collecting ducts are two possible pathophysiologic mechanisms of HPN occurrence.

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Montiel, Virginie, Ramona Bella, Lauriane Y. M. Michel, Hrag Esfahani, Delphine De Mulder, Emma L. Robinson, Jean-Philippe Deglasse, et al. "Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide." Science Translational Medicine 12, no. 564 (October 7, 2020): eaay2176. http://dx.doi.org/10.1126/scitranslmed.aay2176.

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Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but strategies using systemic antioxidants have generally failed to prevent it. We sought to identify key regulators of oxidant-mediated cardiac hypertrophy amenable to targeted pharmacological therapy. Specific isoforms of the aquaporin water channels have been implicated in oxidant sensing, but their role in heart muscle is unknown. RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalized with NADPH oxidase-2 and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of the AQP1 intrasubunit pore inhibited H2O2 transport in mouse and human cells and rescued the myocyte hypertrophy in human induced pluripotent stem cell–derived engineered heart muscle. Treatment of mice with a clinically approved AQP1 inhibitor, Bacopaside, attenuated cardiac hypertrophy. We conclude that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 by the water channel AQP1 and that inhibitors of AQP1 represent new possibilities for treating hypertrophic cardiomyopathies.

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Agre, P., G. M. Preston, B. L. Smith, J. S. Jung, S. Raina, C. Moon, W. B. Guggino, and S. Nielsen. "Aquaporin CHIP: the archetypal molecular water channel." American Journal of Physiology-Renal Physiology 265, no. 4 (October 1, 1993): F463—F476. http://dx.doi.org/10.1152/ajprenal.1993.265.4.f463.

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Despite longstanding interest by nephrologists and physiologists, the molecular identities of membrane water channels remained elusive until recognition of CHIP, a 28-kDa channel-forming integral membrane protein from human red blood cells originally referred to as "CHIP28." CHIP functions as an osmotically driven, water-selective pore; 1) expression of CHIP conferred Xenopus oocytes with markedly increased osmotic water permeability but did not allow transmembrane passage of ions or other small molecules; 2) reconstitution of highly purified CHIP into proteoliposomes permitted determination of the unit water permeability, i.e., 3.9 x 10(9) water molecules.channel subunit-1 x s-1. Although CHIP exists as a homotetramer in the native red blood cell membrane, site-directed mutagenesis studies suggested that each subunit contains an individually functional pore that may be reversibly occluded by mercurial inhibitors reacting with cysteine-189. CHIP is a major component of both apical and basolateral membranes of water-permeable segments of the nephron, where it facilitates transcellular water flow during reabsorption of glomerular filtrate. CHIP is also abundant in certain other absorptive or secretory epithelia, including choroid plexus, ciliary body of the eye, hepatobiliary ductules, gall bladder, and capillary endothelia. Distinct patterns of CHIP expression occur at these sites during fetal development and maturity. Similar proteins from other mammalian tissues and plants were later shown to transport water, and the group is now referred to as the "aquaporins." Recognition of CHIP has provided molecular insight into the biological phenomenon of osmotic water movement, and it is hoped that pharmacological modulation of CHIP function may provide novel treatments of renal failure and other clinical problems.

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Yamaguchi, Takeo, Yohei Iwata, Shingo Miura, and Kazumasa Kawada. "Reinvestigation of Drugs and Chemicals as Aquaporin-1 Inhibitors Using Pressure-Induced Hemolysis in Human Erythrocytes." Biological and Pharmaceutical Bulletin 35, no. 11 (2012): 2088–91. http://dx.doi.org/10.1248/bpb.b12-00581.

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14

Choudhary, Sunita, Thomas R. Sinclair, and P. V. Vara Prasad. "Hydraulic conductance of intact plants of two contrasting sorghum lines, SC15 and SC1205." Functional Plant Biology 40, no. 7 (2013): 730. http://dx.doi.org/10.1071/fp12338.

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Low plant hydraulic conductance has been hypothesised as an approach to decrease the rate of soil water use, resulting in soil water conservation for use during late season water deficits. The impact of leaf hydraulic conductance (Kleaf) on water use characteristics was explored by comparing two sorghum (Sorghum bicolor (L.) Moench) genotypes that had been found to differ in Kleaf. Genotype SC15 had a much lower leaf conductance than genotype SC1205. Four sets of experiments were undertaken to extend the comparison to the impact of differences in Kleaf on the plant water budget. (1) Measurements of hydraulic conductance of intact plants confirmed that leaf conductance of SC15 was lower than that of SC1205. (2) The low leaf conductance of SC15 was associated with a decrease in transpiration during soil drying at a higher soil water content than that of SC1205. (3) SC15 had a restricted transpiration rate at vapour pressure deficits (VPD) above 2.1 kPa, whereas SC1205 did not. (4) Treatment with aquaporin inhibitors showed substantial differences in the sensitivity of the transpiration response between the genotypes. These results demonstrated that low Kleaf in SC15 was associated with conservative water use by restricting transpiration at higher soil water content during soil drying and under high VPD. Tests with inhibitors indicate that these differences may be linked to differences between their aquaporin populations. The differences between the two genotypes indicated that the traits exhibited by SC15 would be desirable in environments where soil water deficits develop.

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Tanski, Damian, Agnieszka Skowronska, Malgorzata Tanska, Ewa Lepiarczyk, and Mariusz T. Skowronski. "The In Vitro Effect of Steroid Hormones, Arachidonic Acid, and Kinases Inhibitors on Aquaporin 1, 2, 5, and 7 Gene Expression in the Porcine Uterine Luminal Epithelial Cells during the Estrous Cycle." Cells 10, no. 4 (April 7, 2021): 832. http://dx.doi.org/10.3390/cells10040832.

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Aquaporins (AQPs) are integral membrane proteins, which play an important role in water homeostasis in the uterus. According to the literature, the expression of aquaporins in reproductive structures depends on the local hormonal milieu. The current study investigated the effect of selected PKA kinase inhibitor H89 and MAPK kinase inhibitor PD98059, on the expression of AQP1, 2, 5, and 7, and steroid hormones (E2), progesterone (P4), and arachidonic acid (AA) in the porcine endometrium on days 18–20 and 2–4 of the estrous cycle (the follicular phase where estrogen and follicle-stimulating hormone (FSH) are secreted increasingly in preparation for estrus and the luteal phase where the ovarian follicles begin the process of luteinization with the formation of the corpus luteum and progesterone secretion, respectively). The luminal epithelial cells were incubated in vitro in the presence of the aforementioned factors. The expression of mRNA was determined by the quantitative real-time PCR technique. In general, in Experiment 1, steroid hormones significantly increased expression of AQP1, 2, and 5 while arachidonic acid increased expression of AQP2 and AQP7. On the other hand, MAPK kinase inhibitor significantly decreased the expression of AQP1 and 5. In Experiment 2, E2, P4, or AA combined with kinase inhibitors differentially affected on AQPs expression. E2 in combination with PKA inhibitor significantly decreased expression of AQP1 but E2 or P4 combined with this inhibitor increased the expression of AQP5 and 7. On the contrary, E2 with PD98059 significantly increased AQP5 and AQP7 expression. Progesterone in combination with MAPK kinase inhibitor significantly downregulated the expression of AQP5 and upregulated AQP7. Arachidonic acid mixed with H89 or PD98059 caused a decrease in the expression of AQP5 and an increase of AQP7. The obtained results indicate that estradiol, progesterone, and arachidonic acid through PKA and MAPK signaling pathways regulate the expression of AQP1 and AQP5 in the porcine luminal epithelial cells in the periovulatory period.

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Lehmann, Guillermo L., Flavia I. Carreras, Leandro R. Soria, Sergio A. Gradilone, and Raúl A. Marinelli. "LPS induces the TNF-α-mediated downregulation of rat liver aquaporin-8: role in sepsis-associated cholestasis." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 2 (February 2008): G567—G575. http://dx.doi.org/10.1152/ajpgi.00232.2007.

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Although bacterial lipopolysaccharides (LPS) are known to cause cholestasis in sepsis, the molecular mechanisms accounting for this effect are only partially known. Because aquaporin-8 (AQP8) seems to facilitate the canalicular osmotic water movement during hepatocyte bile formation, we studied its gene and functional expression in LPS-induced cholestasis. By subcellular fractionation and immunoblotting analysis, we found that 34-kDa AQP8 was significantly decreased by 70% in plasma (canalicular) and intracellular (vesicular) liver membranes. However, expression and subcellular localization of hepatocyte sinusoidal AQP9 were unaffected. Immunohistochemistry for liver AQPs confirmed these observations. Osmotic water permeability ( Pf) of canalicular membranes, measured by stopped-flow spectrophotometry, was significantly reduced (65 ± 1 vs. 49 ± 1 μm/s) by LPS, consistent with defective canalicular AQP8 functional expression. By Northern blot analysis, we found that 1.5-kb AQP8 mRNA expression was increased by 80%, suggesting a posttranscriptional mechanism of protein reduction. The tumor necrosis factor-α (TNF-α) receptor fusion protein TNFp75:Fc prevented the LPS-induced impairment of AQP8 expression and bile flow, suggesting the cytokine TNF-α as a major mediator of LPS effect. Accordingly, studies in hepatocyte primary cultures indicated that recombinant TNF-α downregulated AQP8. The effect of TNF-α was prevented by the lysosomal protease inhibitors leupeptin or chloroquine or by the proteasome inhibitors MG132 or lactacystin, suggesting a cytokine-induced AQP8 proteolysis. In conclusion, our data suggest that LPS induces the TNF-α-mediated posttranscriptional downregulation of AQP8 functional expression in hepatocytes, a mechanism potentially relevant to the molecular pathogenesis of sepsis-associated cholestasis.

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Gros, Stephanie J., Stefan G. Holland-Cunz, Claudiu T. Supuran, and Olivier Braissant. "Personalized Treatment Response Assessment for Rare Childhood Tumors Using Microcalorimetry–Exemplified by Use of Carbonic Anhydrase IX and Aquaporin 1 Inhibitors." International Journal of Molecular Sciences 20, no. 20 (October 9, 2019): 4984. http://dx.doi.org/10.3390/ijms20204984.

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We present a novel approach to a personalized therapeutic concept for solid tumors. We illustrate this on a rare childhood tumor for which only a generalized treatment concept exists using carbonic anhydrase IX and aquaporin 1 inhibitors. The use of microcalorimetry as a refined in vitro method for evaluation of drug susceptibility in organotypic slice culture has not previously been established. Rapid microcalorimetric drug response assessment can refine a general treatment concept when it is applied in cases in which tumors do not respond to conventional chemo-radiation treatment. For solid tumors, which do not respond to classical treatment, and especially for rare tumors without an established protocol rapid microcalorimetric drug response testing presents an elegant novel approach to test alternative therapeutic approaches. While improved treatment concepts have led to improved outcome over the past decades, the prognosis of high risk disease is still poor and rethinking of clinical trial design is necessary. A small patient population combined with the necessity to assess experimental therapies for rare solid tumors rather at the time of diagnosis than in relapsed or refractory patients provides great challenges. The possibility to rapidly compare established protocols with innovative therapeutics presents an elegant novel approach to refine and personalize treatment.

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Nørregaard, Rikke, Boye L. Jensen, Sukru Oguzkan Topcu, Guixian Wang, Horst Schweer, Søren Nielsen, and Jørgen Frøkiær. "Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 298, no. 4 (April 2010): R1017—R1025. http://dx.doi.org/10.1152/ajpregu.00336.2009.

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Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE2, PGF2α, 6-keto-PGF1α, PGD2, and thromboxane (Tx) B2 concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE2, 6-keto-PGF1α, and PGF2α was increased at 6 h BUO, and PGE2 and PGF2α increased further at 12 h BUO. TxB2 increased after 12 h BUO. 6-keto-PGF1α remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE2, TxB2, 6-keto-PGF1α, and PGF2α below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE2, PGF2α, and PGD2 in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE2 and 6-keto-PGF1α concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF1α and TxB2 concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE2 and PGF2α with minor, but significant, contributions from COX-1. PGD2 synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.

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Tomita, Yoko, Helen M. Palethorpe, Eric Smith, Maryam Nakhjavani, Amanda R. Townsend, Timothy J. Price, Andrea J. Yool, and Jennifer E. Hardingham. "Bumetanide-Derived Aquaporin 1 Inhibitors, AqB013 and AqB050 Inhibit Tube Formation of Endothelial Cells through Induction of Apoptosis and Impaired Migration In Vitro." International Journal of Molecular Sciences 20, no. 8 (April 12, 2019): 1818. http://dx.doi.org/10.3390/ijms20081818.

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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.

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Bradford, Davis, Viswanathan Raghuram, Justin L. L. Wilson, Chung-Lin Chou, Jason D. Hoffert, Mark A. Knepper, and Trairak Pisitkun. "Use of LC-MS/MS and Bayes' theorem to identify protein kinases that phosphorylate aquaporin-2 at Ser256." American Journal of Physiology-Cell Physiology 307, no. 2 (July 15, 2014): C123—C139. http://dx.doi.org/10.1152/ajpcell.00377.2012.

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In the renal collecting duct, binding of AVP to the V2 receptor triggers signaling changes that regulate osmotic water transport. Short-term regulation of water transport is dependent on vasopressin-induced phosphorylation of aquaporin-2 (AQP2) at Ser256. The protein kinase that phosphorylates this site is not known. We use Bayes' theorem to rank all 521 rat protein kinases with regard to the likelihood of a role in Ser256 phosphorylation on the basis of prior data and new experimental data. First, prior probabilities were estimated from previous transcriptomic and proteomic profiling data, kinase substrate specificity data, and evidence for kinase regulation by vasopressin. This ranking was updated using new experimental data describing the effects of several small-molecule kinase inhibitors with known inhibitory spectra (H-89, KN-62, KN-93, and GSK-650394) on AQP2 phosphorylation at Ser256 in inner medullary collecting duct suspensions. The top-ranked kinase was Ca2+/calmodulin-dependent protein kinase II (CAMK2), followed by protein kinase A (PKA) and protein kinase B (AKT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based in vitro phosphorylation studies compared the ability of three highly ranked kinases to phosphorylate AQP2 and other inner medullary collecting duct proteins, PKA, CAMK2, and serum/glucocorticoid-regulated kinase (SGK). All three proved capable of phosphorylating AQP2 at Ser256, although CAMK2 and PKA were more potent than SGK. The in vitro phosphorylation experiments also identified candidate protein kinases for several additional phosphoproteins with likely roles in collecting duct regulation, including Nedd4-2, Map4k4, and 3-phosphoinositide-dependent protein kinase 1. We conclude that Bayes' theorem is an effective means of integrating data from multiple data sets in physiology.

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Agbani, Ejaife O., and Alastair W. Poole. "Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis." Blood 130, no. 20 (November 16, 2017): 2171–79. http://dx.doi.org/10.1182/blood-2017-05-787259.

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Abstract Current understanding of how platelets localize coagulation to wound sites has come mainly from studies of a subpopulation of activated platelets. In this review, we summarize data from the last 4 decades that have described these platelets with a range of descriptive titles and attributes. We identify striking overlaps in the reported characteristics of these platelets, which imply a single subpopulation of versatile platelets and thus suggest that their commonality requires unification of their description. We therefore propose the term procoagulant platelet as the unifying terminology. We discuss the agonist requirements and molecular drivers for the dramatic morphological transformation platelets undergo when becoming procoagulant. Finally, we provide perspectives on the biomarker potential of procoagulant platelets for thrombotic events as well as on the possible clinical benefits of inhibitors of carbonic anhydrase enzymes and the water channel Aquaporin-1 for targeting this subpopulation of platelets as antiprocoagulant antithrombotics.

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Yip, Kay-Pong. "Epac-mediated Ca2+ mobilization and exocytosis in inner medullary collecting duct." American Journal of Physiology-Renal Physiology 291, no. 4 (October 2006): F882—F890. http://dx.doi.org/10.1152/ajprenal.00411.2005.

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PKA has traditionally been thought as the binding protein of cAMP for mediating arginine vasopressin (AVP)-regulated osmotic water permeability in kidney collecting duct. It is now known that cAMP also exerts its effects via Epac (exchange protein directly activated by cAMP) and that intracellular Ca2+ mobilization is necessary for AVP-induced apical exocytosis in inner medullary collecting duct (IMCD). The role of Epac as an effector of cAMP action in addition to PKA was investigated using confocal fluorescence microscopy in perfused IMCD. PKA inhibitors (1 μM H-89 or 10 μM KT-5720) at concentrations known to inhibit aquaporin-2 (AQP2) phosphorylation did not prevent AVP-induced Ca2+ mobilization and oscillations. Epac-selective cAMP agonist (8-pCPT-2′- O-Me-cAMP) mimicked AVP in triggering Ca2+ mobilization and oscillations, which was blocked by ryanodine but not by Rp-cAMP (a competitive antagonist of cAMP binding to PKA). 8-pCPT-2′- O-Me-cAMP also triggered apical exocytosis in the presence of a PKA inhibitor. Immunolocalization of AQP2 in perfused IMCD demonstrated that 8-pCPT-2′- O-Me-cAMP induces apical targeting of AQP2 and that AQP2 is abundant in junctional regions of basolateral membrane. Immunofluorescence study also confirmed the presence of Epac (isoform I) in IMCD. These results indicate that activation of Epac by an exogenous cAMP analog triggers intracellular Ca2+ mobilization and apical exocytotic insertion of AQP2 in IMCD.

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Diepens, Robin J. W., Els den Dekker, Marcelle Bens, A. Freek Weidema, Alain Vandewalle, René J. M. Bindels, and Joost G. J. Hoenderop. "Characterization of a murine renal distal convoluted tubule cell line for the study of transcellular calcium transport." American Journal of Physiology-Renal Physiology 286, no. 3 (March 2004): F483—F489. http://dx.doi.org/10.1152/ajprenal.00231.2003.

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To unravel the molecular regulation of renal transcellular Ca2+ transport, a murine distal convoluted tubule (mpkDCT) cell line derived from distal convoluted tubules (DCT) microdissected from a SV-PK/Tag transgenic mouse was characterized. This cell line originated from DCT only, as mRNA encoding for the DCT marker thiazide-sensitive Na+/Cl- cotransporter was expressed, whereas mRNA encoding for the connecting tubule and collecting duct marker aquaporin-2 was not detected, as determined by reverse-transcriptase PCR. mpkDCT cells expressed mRNA encoding the Ca2+ channels TRPV5 and TRPV6 and other key players necessary for transcellular Ca2+ transport, i.e., calbindin-D9k, calbindin-D28k, plasma membrane Ca2+-ATPase isoform 1b, and Na+/Ca2+ exchanger 1. Primary cultures of DCT cells exhibited net transcellular Ca2+ transport of 0.4 ± 0.1 nmol·h-1·cm-2, whereas net transcellular Ca2+ transport across mpkDCT cells was significantly higher at 2.4 ± 0.4 nmol·h-1·cm-2. Transcellular Ca2+ transport across mpkDCT cells was completely inhibited by ruthenium red, an inhibitor of TRPV5 and TRPV6, but not by the voltage-operated Ca2+ channel inhibitors felodipine and verapamil. With the use of patch-clamp analysis, the IC50 of ruthenium red on Na+ currents was between the values measured for TRPV5- and TRPV6-expressing HEK 293 cells, suggesting that TRPV5 and/or TRPV6 is possibly active in mpkDCT cells. Forskolin in combination with IBMX, 1,25-dihydroxyvitamin D3, and 1-deamino-8-d-arginine vasopressin increased transcellular Ca2+ transport, whereas PMA and parathyroid hormone had no significant effect. In conclusion, the murine mpkDCT cell line provides a unique cell model in which to study the molecular regulation of transcellular Ca2+ transport in the kidney in vitro.

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Choi, Hyo-Jung, Hyo-Ju Jang, Euijung Park, Stine Julie Tingskov, Rikke Nørregaard, Hyun Jun Jung, and Tae-Hwan Kwon. "Sorting Nexin 27 Regulates the Lysosomal Degradation of Aquaporin-2 Protein in the Kidney Collecting Duct." Cells 9, no. 5 (May 13, 2020): 1208. http://dx.doi.org/10.3390/cells9051208.

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Sorting nexin 27 (SNX27), a PDZ (Postsynaptic density-95/Discs large/Zonula occludens 1) domain-containing protein, cooperates with a retromer complex, which regulates intracellular trafficking and the abundance of membrane proteins. Since the carboxyl terminus of aquaporin-2 (AQP2c) has a class I PDZ-interacting motif (X-T/S-X-Φ), the role of SNX27 in the regulation of AQP2 was studied. Co-immunoprecipitation assay of the rat kidney demonstrated an interaction of SNX27 with AQP2. Glutathione S-transferase (GST) pull-down assays revealed an interaction of the PDZ domain of SNX27 with AQP2c. Immunocytochemistry of HeLa cells co-transfected with FLAG-SNX27 and hemagglutinin (HA)-AQP2 also revealed co-localization throughout the cytoplasm. When the PDZ domain was deleted, punctate HA-AQP2 labeling was localized in the perinuclear region. The labeling was intensively overlaid by Lysotracker staining but not by GM130 labeling, a cis-Golgi marker. In rat kidneys and primary cultured inner medullary collecting duct cells, the subcellular redistribution of SNX27 was similar to AQP2 under 1-deamino-8-D-arginine vasopressin (dDAVP) stimulation/withdrawal. Cell surface biotinylation assay showed that dDAVP-induced AQP2 translocation to the apical plasma membrane was unaffected after SNX27 knockdown in mpkCCD cells. In contrast, the dDAVP-induced AQP2 protein abundance was significantly attenuated without changes in AQP2 mRNA expression. Moreover, the AQP2 protein abundance was markedly declined during the dDAVP withdrawal period after stimulation under SNX27 knockdown, which was inhibited by lysosome inhibitors. Autophagy was induced after SNX27 knockdown in mpkCCD cells. Lithium-induced nephrogenic diabetes insipidus in rats revealed a significant downregulation of SNX27 in the kidney inner medulla. Taken together, the PDZ domain-containing SNX27 interacts with AQP2 and depletion of SNX27 contributes to the autophagy-lysosomal degradation of AQP2.

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Parvin, Most Nahid, Shingo Kurabuchi, Kwartarini Murdiastuti, Chenjuan Yao, Chisato Kosugi-Tanaka, Tetsuya Akamatsu, Norio Kanamori, and Kazuo Hosoi. "Subcellular redistribution of AQP5 by vasoactive intestinal polypeptide in the Brunner's gland of the rat duodenum." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 6 (June 2005): G1283—G1291. http://dx.doi.org/10.1152/ajpgi.00030.2004.

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Aquaporin (AQP)5, an exocrine-type water channel, was detected in the rat duodenum by Western blot analysis, and was localized by immunohistochemistry in the secretory granule membranes as well as in the apical and lateral aspects of the plasma membrane of Brunner's gland cells. Incubation of duodenal slices with vasoactive intestinal polypeptide (VIP) in vitro significantly increased the amount of AQP5 in the apical membrane fraction in a dose- and time-dependent manner with the amount reaching a plateau at 100 nM VIP and becoming near maximal after a 30-s incubation. Protein kinase inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7, 50 μM), and N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; PKA-specific, 1 μM) blocked this increase, but PKC-specific inhibitor calphostin C did not, implying the involvement of PKA but not PKC in this cellular event. Intravenous injection with VIP (40 μg/kg body wt) provoked dilation of the lumen of the Brunner's gland at 2 and 7 min and increased the staining intensity of AQP5 in the apical and lateral membranes. AQP1 (both nonglycosylated and glycosylated forms) was also found to localize in the apical and basolateral membranes of cells of Brunner's gland. VIP, however, did not provoke any significant change in the AQP1 level in the apical membrane, as judged from the results of the above in vitro and in vivo experiments. These results suggest that VIP induced the exocytosis of granule contents and simultaneously caused translocation of AQP5 but not of AQP1 to the apical membrane in Brunner's gland cells.

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Uchida, Tomohiko, Masahiro Mori, Akiyuki Uzawa, Hiroki Masuda, Mayumi Muto, Ryohei Ohtani, and Satoshi Kuwabara. "Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption." Multiple Sclerosis Journal 23, no. 8 (September 28, 2016): 1072–84. http://dx.doi.org/10.1177/1352458516672015.

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Background: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood–brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown. Objective: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO. Methods: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients. Results: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions. Conclusion: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).

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Chu, Heling, Xiaobo Yang, Chuyi Huang, Zidan Gao, Yuping Tang, and Qiang Dong. "Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4." Cerebrovascular Diseases 44, no. 1-2 (2017): 10–25. http://dx.doi.org/10.1159/000460261.

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Background: Apelin-13 has been found to have protective effects on many neurological diseases, including cerebral ischemia. However, whether Apelin-13 acts on blood-brain barrier (BBB) disruption following cerebral ischemia is largely unknown. Aquaporin-4 (AQP4) has a close link with BBB due to the high concentration in astrocyte foot processes and regulation of astrocytes function. Here, we aimed to test Apelin-13′s effects on ischemic BBB injury and examine whether the effects were dependent on AQP4. Methods: We detected the expression of AQP4 induced by Apelin-13 injection at 1, 3, and 7 days after middle cerebral artery occlusion. Meanwhile, we examined the effects of Apelin-13 on neurological function, infarct volume, and BBB disruption owing to cerebral ischemia in wild type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the possible signal transduction pathways activated by Apelin-13 to regulate AQP4 expression via astrocyte cultures. Results: It was found that Apelin-13 highly increased AQP4 expression as well as reduced neurological scores and infarct volume. Importantly, Apelin-13 played a role of BBB protection in both types of mice by reducing BBB permeability, increased vascular endothelial growth factor, upregulated endothelial nitric oxide synthase, and downregulated inducible NOS. In morphology, we demonstrated Apelin-13 suppressed tight junction opening and endothelial cell swelling via electron microscopy detection. Meanwhile, Apelin-13 also alleviated apoptosis of astrocytes and promoted angiogenesis. Interestingly, effects of AQP4 on neurological function and infarct volume varied with time course, while AQP4 elicited protective effects on BBB at all time points. Statistical analysis of 2-way analysis of variance with replication indicated that AQP4 was required for these effects. In addition, Apelin-13 upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt as well as AQP4 protein in cultured astrocytes. The latter was inhibited by ERK and phosphatidylinositol 3′-kinase (PI3K) inhibitors. Conclusion: Our data suggest that Apelin-13 protects BBB from disruption after cerebral ischemia both morphologically and functionally, which is highly associated with the increased levels of AQP4, possibly through the activation of ERK and PI3K/Akt pathways. This study provides double targets to protection of ischemic BBB damage, which can present new insights to drugs development.

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Yang, Chun-Yin, Cheng-Chang Pan, Chih-Hua Tseng, and Feng-Lin Yen. "Antioxidant, Anti-Inflammation and Antiaging Activities of Artocarpus altilis Methanolic Extract on Urban Particulate Matter-Induced HaCaT Keratinocytes Damage." Antioxidants 11, no. 11 (November 21, 2022): 2304. http://dx.doi.org/10.3390/antiox11112304.

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Particulate matter (PM) is one of the reasons that exacerbate skin diseases. Impaired barrier function is a common symptom in skin diseases, including atopic dermatitis, eczema and psoriasis. Herbal extracts rich in antioxidants are thought to provide excellent pharmacological activities; however, the anti-pollution activity of Artocarpus altilis extract (AAM) has not been investigated yet. The present study demonstrated that 5 μg/mL of AAM was considered to be a safe dose for further experiments without cytotoxicity. Next, we evaluated the anti-pollution activity of AAM through the PM-induced keratinocytes damage cell model. The results showed that AAM could reduce PM-induced overproduction of intracellular ROS and the final product of lipid peroxidation, 4-hydroxynonenal (4HNE). In addition, AAM not only reduced the inflammatory protein expressions, including tumor necrosis factor α (TNFα), TNF receptor 1 (TNFR1) and cyclooxygenase-2 (COX-2), but also balanced the aging protein ratio of matrix metalloproteinase (MMPs) and tissue inhibitors of metalloproteases (TIMPs) through downregulating the phosphorylation of mitogen-activated protein kinase (MAPK) signaling. For skin barrier protection, AAM could repair PM-induced barrier function proteins damage, including filaggrin, loricrin and aquaporin 3 for providing anti-aging bioactivity. In conclusion, AAM has the potential to be developed as an anti-pollution active ingredient for topical skin products to prevent skin oxidation, inflammation and aging, and restore the skin barrier function.

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Miyazawa, Shin-Ichi, Satomi Yoshimura, Yuki Shinzaki, Masayoshi Maeshima, and Chikahiro Miyake. "Deactivation of aquaporins decreases internal conductance to CO2 diffusion in tobacco leaves grown under long-term drought." Functional Plant Biology 35, no. 7 (2008): 553. http://dx.doi.org/10.1071/fp08117.

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We compared the diffusion conductance to CO2 from the intercellular air space to the chloroplasts (internal conductance (g i)) between tobacco leaves acclimated to long-term drought (drought-acclimated (DA)) and those grown under sufficient irrigation (well-watered (WW)), and analysed the changes in g i in relation to the leaf anatomical characteristics and a possible CO2 transporter, aquaporin. The g i, which was estimated by combined analyses of CO2 gas exchange with chlorophyll fluorescence, in the DA plants was approximately half of that in the WW plants. The mesophyll and chloroplast surface areas exposing the intercellular air space, which potentially affect g i, were not significantly different between the WW and DA plants. The amounts of plasma membrane aquaporins (PIP), immunochemically determined using radish PIP antibodies, were unrelated to g i. After treatment with HgCl2, an aquaporin inhibitor, the water permeability of the leaf tissues (measured as the weight loss of fully-turgid leaf disks without the abaxial epidermis in 1 m sorbitol) in WW plants decreased with an increase in HgCl2 concentration. The g i in the WW plants decreased to similar levels to the DA plants when the detached leaflets were fed with 0.5 mm HgCl2. In contrast, both water permeability and g i were insensitive to HgCl2 treatments in DA plants. These results suggest that deactivation of aquaporins is responsible for the significant reduction in g i observed in plants growing under long-term drought.

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Piraino, Lindsay R., Danielle S. W. Benoit, and Lisa A. DeLouise. "Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions." Cells 10, no. 7 (July 8, 2021): 1723. http://dx.doi.org/10.3390/cells10071723.

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Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren’s syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel®, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor β receptor (TGFβR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands.

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Li, Ming, Yu-Bo Xiao, Le Wei, Qi Liu, Pin-Yue Liu, and Jian-Feng Yao. "Beneficial Effects of Traditional Chinese Medicine in the Treatment of Premature Ovarian Failure." Evidence-Based Complementary and Alternative Medicine 2022 (November 26, 2022): 1–12. http://dx.doi.org/10.1155/2022/5413504.

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Premature ovarian failure (POF) is characterized by hormonal disorders, amenorrhea, and premature loss of fertility potential in women of reproductive age. Several studies have been conducted on the effectiveness of traditional Chinese medicine (TCM) in treating POF. TCM relied primarily on apoptosis, immunity, and aging to treat POF based on the studies of domestic and foreign literature. Zuogui pills inhibited mitochondrial-dependent apoptosis in the treatment of POF. Huyang Yangkun formula regulated the downstream of the Bcl-2 family to resist apoptosis through the aquaporin-1 protein. Modified Bazhen decoction regulated apoptosis in POF by regulating X-linked inhibitors of apoptosis protein. Bushen Tianjing recipe was effective in treating POF by promoting angiogenesis and preventing apoptosis. As for immunity, Bushen Jianpi prescription and Er-Xian decoction cured autoimmunity POF models and increased follicular development-related protein expression. Bushen Huoxue Tang improved ovarian function and reduced ovarian inflammation by regulating the Nrf2/Keap1 signaling pathway and T lymphocytes. Taohong Siwu decoction promoted the proliferation and differentiation of granulosa cells of POF mice by regulating the TGF-β1/Smads signaling pathway. In addition, ginsenoside Rg1 and Jiajian Guisheng formula treated POF by regulating cell aging-related mechanisms. Si Wu Tang treated POF by activating the angiogenesis-related proteins. The goal of this review is to serve as a reference for in-depth research into the treatment of POF with TCM and provide inspiration for new diagnostic methods and treatment options.

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Belimov, Andrey A., Vera I. Safronova, and Ian C. Dodd. "Water relations responses of the pea (Pisum sativum L.) mutant SGECdt to mercury." BIO Web of Conferences 23 (2020): 01003. http://dx.doi.org/10.1051/bioconf/20202301003.

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Mercury (Hg) is one of the most toxic heavy metals and has multiple impacts on plant growth and physiology, including disturbances of plant water status. The impact of Hg on water relations was assessed by exposing the unique Hg-sensitive pea (Pisum sativum L.) mutant SGECdt and its wild-type (WT) line SGE in hydroponic culture. When the plants were grown in the presence of 1 or 2 µM HgCl2 for 11 days, the SGECdt mutant had lower whole plant transpiration rate and increased leaf temperature, indicating stomatal closure. Shoot removal of Hg-untreated plants resulted in greater root-pressure induced xylem sap flow in the SGECdt mutant than WT plants. Treating these plants with 50 µM HgCl2 (an inhibitor of aquaporins) for 1 h decreased xylem sap flow of both genotypes by about 5 times and eliminated differences between WT and mutant. Adding 1 mM dithiothreitol (the reducing thiol reagent used for opening aquaporins) to the nutrient solution of Hg-treated plants partially restored xylem sap flow in SGECdt roots only, suggesting genotypic differences in aquaporin function. Thus root water uptake is important in mediating sensitivity of SGECdt to toxic Hg.

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Müller, E. Matthias, Jochen S. Hub, Helmut Grubmüller, and Bert L. de Groot. "Is TEA an inhibitor for human Aquaporin-1?" Pflügers Archiv - European Journal of Physiology 456, no. 4 (January 15, 2008): 663–69. http://dx.doi.org/10.1007/s00424-007-0422-0.

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MARKERT, JAMES M., CATHERINE M. FULLER, G. YANCEY GILLESPIE, JAMES K. BUBIEN, LEE ANNE McLEAN, ROBERT L. HONG, KAILIN LEE, STEVEN R. GULLANS, TIMOTHY B. MAPSTONE, and DALE J. BENOS. "Differential gene expression profiling in human brain tumors." Physiological Genomics 5, no. 1 (February 7, 2001): 21–33. http://dx.doi.org/10.1152/physiolgenomics.2001.5.1.21.

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Gene expression profiling of three human temporal lobe brain tissue samples (normal) and four primary glioblastoma multiforme (GBM) tumors using oligonucleotide microarrays was done. Moreover, confirmation of altered expression was performed by whole cell patch clamp, immunohistochemical staining, and RT-PCR. Our results identified several ion and solute transport-related genes, such as N-methyl-d-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-2 receptors, GABAA receptor subunits α3, β1, β2, and β3, the glutamate transporter, the glutamate/aspartate transporter II, the potassium channel KV2.1, hKVβ3, and the sodium/proton exchanger 1 (NHE-1), that are all downregulated in the tumors compared with the normal tissues. In contrast, aquaporin-1, possibly aquaporins-3 and -5, and GLUT-3 message appeared upregulated in the tumors. Our results also confirmed previous work showing that osteopontin, nicotinamide N-methyltransferase, murine double minute 2 (MDM2), and epithelin (granulin) are upregulated in GBMs. We also demonstrate for the first time that the cytokine and p53 binding protein, macrophage migration inhibitory factor (MIF), appears upregulated in GBMs. These results indicate that the modulation of ion and solute transport genes and heretofore unsuspected cytokines (i.e., MIF) may have profound implications for brain tumor cell biology and thus may identify potential useful therapeutic targets in GBMs.

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Frank, L. A., R. D. Rose, M. R. Anastasi, T. C. Y. Tan, M. F. Barry, J. G. Thompson, and H. M. Brown. "Artificial blastocyst collapse prior to vitrification significantly improves Na+/K+-ATPase-dependent post-warming blastocoel re-expansion kinetics without inducing endoplasmic reticulum stress gene expression in the mouse." Reproduction, Fertility and Development 31, no. 2 (2019): 294. http://dx.doi.org/10.1071/rd17500.

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Blastocoel expansion during embryo development is known to be reliant on the Na+/K+-ATPase pump, but little is known about the relative contribution of active (Na+/K+-ATPase pump) and facilitated diffusion (aquaporins) water transport during blastocoel re-expansion after vitrification. The aims of this study were to examine potential effects of artificial blastocoel collapse (ABC) on markers of embryo stress and the contribution of active and facilitated diffusion water transport mechanisms to blastocoel re-expansion. Day 5 mouse embryos were vitrified using either a standard protocol, laser pulse ABC, a hyperosmotic sucrose ABC protocol or both laser pulse and sucrose. Using real-time polymerase chain reaction, no differences were found in the gene expression of the endoplasmic reticulum (ER) stress markers activating transcription factor 4 (Atf4) or heat shock protein 90-alpha (Hsp90α) 2h after warming. Similarly, expression of the Na+/K+-ATPase pump gene, ATPase, Na+/K+ transporting, beta 1 polypeptide (Atp1b1) and protein did not differ between groups. Aquaporin 8 (Aqp8) gene expression was significantly lower in the laser+sucrose ABC group than in fresh controls, and aquaporin 3 (Aqp3) expression significantly higher in standard vitrified embryos compared with all other groups. Ouabain, a potent and specific Na+/K+-ATPase pump inhibitor, inhibited blastocoel re-expansion in both standard protocol- and laser ABC-vitrified embryos, reducing both groups to the same rate of re-expansion 3h after warming. These results demonstrate that ABC before vitrification does not alter mRNA or protein expression of Na+/K+-ATPase, or mRNA levels of ER stress genes Atf4 and Hsp90α. Activity of the pump may be increased in ABC embryos, with potential compensation by AQP3 when it is compromised.

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Effros, R. M., C. Darin, E. R. Jacobs, R. A. Rogers, G. Krenz, and E. E. Schneeberger. "Water transport and the distribution of aquaporin-1 in pulmonary air spaces." Journal of Applied Physiology 83, no. 3 (September 1, 1997): 1002–16. http://dx.doi.org/10.1152/jappl.1997.83.3.1002.

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Effros, R. M., C. Darin, E. R. Jacobs, R. A. Rogers, G. Krenz, and E. E. Schneeberger. Water transport and the distribution of aquaporin-1 in pulmonary air spaces. J. Appl. Physiol. 83(3): 1002–1016, 1997.—Recent evidence suggests that water transport between the pulmonary vasculature and air spaces can be inhibited by HgCl2, an agent that inhibits water channels (aquaporin-1 and -5) of cell membranes. In the present study of isolated rat lungs, clearances of labeled (3HOH) and unlabeled water were compared after instillation of hypotonic or hypertonic solutions into the air spaces or injection of a hypotonic bolus into the pulmonary artery. The clearance of 3HOH between the air spaces and perfusate after intratracheal instillation and from the vasculature to the tissues after pulmonary arterial injections was invariably greater than that of unlabeled water, indicating that osmotically driven transport of water is limited by permeability of the tissue barriers rather than the rate of perfusion. Exposure to 0.5 mM HgCl2 in the perfusate and air-space solution reduced the product of the filtration coefficient and surface area ( P f S) of water from the air spaces to the perfusate by 28% after instillation of water into the trachea. In contrast, perfusion of 0.5 mM HgCl2 in air-filled lungs reduced P f Sof the endothelium by 86% after injections into the pulmonary artery, suggesting that much of the action of this inhibitor is on the endothelial surfaces. Confocal laser scanning microscopy demonstrated that aquaporin-1 is on mouse pulmonary endothelium. No aquaporin-1 was found on alveolar type I cells with immunogold transmission electron microscopy, but small amounts were present on some type II cells.

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Hadrup, Niels, Jørgen S. Petersen, Jeppe Praetorius, Eddi Meier, Martin Græbe, Lone Brønd, Dennis Staahltoft, et al. "Opioid receptor-like 1 stimulation in the collecting duct induces aquaresis through vasopressin-independent aquaporin-2 downregulation." American Journal of Physiology-Renal Physiology 287, no. 1 (July 2004): F160—F168. http://dx.doi.org/10.1152/ajprenal.00329.2003.

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Nociceptin, the endogenous ligand of the inhibitory G protein-coupled opioid receptor-like 1 receptor, produces aquaresis (i.e., increases the excretion of solute-free urine) in rats. However, the mechanism underlying this effect has not yet been explained. Using immunohistochemistry, we found the opioid receptor-like 1 receptor in the rat kidney colocalized with the vasopressin-regulated water channel aquaporin-2 in inner medullary collecting ducts. We investigated the aquaretic effect of opioid receptor-like 1 receptor stimulation by infusing the selective nociceptin analog ZP120C; volume depletion was prevented by computer-driven, servo-controlled intravenous volume replacement with 50 mM glucose. ZP120C induced a marked and sustained aquaresis in normal and congestive heart failure rats in the absence of changes in vasopressin plasma concentrations. The ZP120C-induced aquaresis was associated with downregulation of the aquaporin-2 protein level in both rat groups, suggesting that opioid receptor-like 1 receptor stimulation produces aquaresis by inhibiting the vasopressin type-2 receptor-mediated stimulation on collecting duct water reabsorption. However, substantial amounts of PKA-mediated serine 256 phosphorylated aquaporin-2 were still present after 4 h of ZP120C treatment. Furthermore, neither preincubation with nociceptin nor ZP120C inhibited vasopressin-mediated cAMP accumulation in isolated collecting ducts. We conclude that renal opioid receptor-like 1 receptor stimulation in normal and congestive heart failure rats produces aquaresis by a direct renal effect, via aquaporin-2 downregulation, through a mechanism not involving inhibition of vasopressin type-2 receptor-mediated cAMP production.

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Lin, Yu, Tiezheng Zhang, Pinning Feng, Miaojuan Qiu, Qiaojuan Liu, Suchun Li, Peili Zheng, et al. "Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus." American Journal of Physiology-Renal Physiology 313, no. 4 (October 1, 2017): F914—F925. http://dx.doi.org/10.1152/ajprenal.00553.2016.

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The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food−1·day−1 for 4 days and 20 mmol·kg dry food−1·day−1 for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt−1·day−1 in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.

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Murase, Takashi, Ying Tian, Xiao Ying Fang, and Joseph G. Verbalis. "Synergistic effects of nitric oxide and prostaglandins on renal escape from vasopressin-induced antidiuresis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 284, no. 2 (February 1, 2003): R354—R362. http://dx.doi.org/10.1152/ajpregu.00065.2002.

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Recent results from our laboratories indicate that renal escape from AVP-induced antidiuresis is accompanied by marked downregulation of kidney aquaporin-2 (AQP2) and AVP V2 receptors. The present studies evaluated the effect of nitric oxide (NO) and PG synthesis blockade on escape from antidiuresis. dDAVP-infused rats were water loaded (WL) for 5 days. l-NAME, an NO synthesis inhibitor, or diclofenac, a cyclooxygenase inhibitor, was infused subcutaneously beginning 1 day before WL. As early as 2 days after WL, urine volume increased and urine osmolality decreased, indicating the onset of escape. Endogenous NO synthesis, measured as urinary NO2 + NO3 excretion, was significantly increased in the WL group compared with the non-WL controls during all 5 days of WL. l-NAME (20 mg · kg−1 · day−1) markedly decreased urine volume on days 4 and 5of WL, indicating inhibition of the escape phenomenon. Kidney AQP2 protein was significantly increased by this dose ofl-NAME as well. A lower dose of l-NAME (10 mg · kg−1 · day−1) or diclofenac (2.5 mg · kg−1 · day−1) did not significantly affect the escape phenomenon by itself, but the combination of l-NAME and diclofenac showed a marked inhibitory effect on the escape phenomenon, which was also accompanied by a significant increase in kidney AQP2 expression. These results therefore suggest that renal NO and PG both play important roles in escape from AVP-induced antidiuresis by acting synergistically to downregulate kidney AQP2 expression.

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Orce, Gabriel, Graciela Castillo, Yolanda Chanampa, and Alejandra Bellomio. "Permeability to water in a tight epithelium: possible modulating action of gap junctions." Canadian Journal of Physiology and Pharmacology 82, no. 6 (May 1, 2004): 417–21. http://dx.doi.org/10.1139/y04-037.

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Osmotic water flow (Jw) across tight distal nephron epithelial membranes increases upon exposure to vasopressin: following binding of the hormone to its receptors, intracellular cyclic AMP concentration increases, leading to insertion of aquaporins in the apical membrane. The involvement of intercellular communication in the process, however, has not been adequately explored. Octanol, 1.2 × 103 M, a gap junction inhibitor, significantly reduced Jw (expressed as mg·20 min1) in isolated toad urinary bladders (a model of the distal nephron) subjected to a transepithelial osmotic gradient and exposed to agents mimicking the vasopressin-triggered mechanism: oxytocin, 50 mIU·mL1 (from 185.3 ± 28.0, P < 0.001, to 69.0 ± 23.6, P < 0.05; Pdiff < 0.01, n = 6), and cyclic AMP, 2.5 × 103 M (from 98.0 ± 32.6, P < 0.02, to 31.0 ± 13.9, NS; Pdiff < 0.05, n = 12), without altering the effect of nystatin, 450 U·mL1, which increases Jw via a mechanism unrelated to apical aquaporin insertion (163.2 ± 16.3, P < 0.001, in controls vs. 150.3 ± 10.4, P < 0.001, in octanol-treated bladders; Pdiff: NS, n = 6). Another gap junction blocker, carbenoxolone, 2.0 × 104 M (CBX), exerted similar effects on the responses to oxytocin, 100 mIU·mL1, reducing the response from 256.7 ± 33.6, P < 0.001, to 102.7 ± 10.4, P < 0.001; Pdiff < 0.01, n = 6) and nystatin, which was unaffected (95.0 ± 20.9, P < 0.01, vs. 132.0 ± 27.0, P < 0.01; Pdiff: NS, n = 6). Our results suggest that either gap junctions or, alternatively, unapposed gap junction hemichannels, may be important in the regulation of Jw in the isolated toad bladder, by modulating a step in the physiological process leading to increased apical membrane permeability. Key words: Bufo arenarum, toad urinary bladder, water flow, epithelial permeability, n-octanol, carbenoxolone.

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Igarashi, Hironaka, Vincent J. Huber, Mika Tsujita, and Tsutomu Nakada. "Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema." Neurological Sciences 32, no. 1 (October 6, 2010): 113–16. http://dx.doi.org/10.1007/s10072-010-0431-1.

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Nicosia, Michael, Ran Fan, Satoshi Miyairi, George W. Farr, Paul R. McGuirk, Marc F. Pelletier, Ashley Beavers, and Anna Valujskikh. "Aquaporin 4 blockade alters T cell trafficking through a novel mechanism of S1PR1 regulation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 55.33. http://dx.doi.org/10.4049/jimmunol.200.supp.55.33.

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Abstract The water channels aquaporins mediate a variety of immune functions. We previously demonstrated that aquaporin 4 (AQP4) is expressed by CD4 and CD8 T cells and blockade of AQP4 with small molecule inhibitor AER-270/271 significantly prolongs survival of heart allografts in two robust models of rejection. The goal of this study was to determine the effects of AQP4 blockade on T cells. Administration of AER-271 into naïve non-transplanted mice (250 μg i.p. every 6 h on d. 0–4) decreased numbers of circulating CD4 and CD8 T cells, but not B cells, by >90%, compared to untreated controls. The T cell frequencies and numbers in the secondary lymphoid organs (SLOs) were not significantly affected by AER-271, suggesting the lack of circulating T cells is not due to systemic depletion but rather to altered T cell trafficking. The effect of AER-271 treatment was transient, as circulating T cell numbers returned to pretreatment levels by d 21. AER-271 treated animals promptly rejected heart allografts transplanted 24 d after treatment cessation (MST 6 d, n=4). We next tested the effects of AQP4 blockade on Sphingosine-1 Phosphate Receptor 1 (S1PR1), a key mediator of T cell trafficking. S1PR1 mRNA expression was reduced in isolated mouse spleen T cells within 3 h of in vitro incubation with AER-270. Decreased S1PR1 mRNA expression translated into altered chemotaxis, as AER-270 reduced T cell migration toward S1PR1 ligand, Sphingosine-1 Phosphate (S1P), in a transwell system. Our data suggest that AER-270/271 treatment results in altered S1PR1 transcription thus changing T cell trafficking and prolonging allograft survival. Therefore, AQP4 blockade may be an attractive therapeutic strategy in transplantation and other immune-mediated diseases.

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Palethorpe, Helen, Yoko Tomita, Eric Smith, Jinxin Pei, Amanda Townsend, Timothy Price, Joanne Young, Andrea Yool, and Jennifer Hardingham. "The Aquaporin 1 Inhibitor Bacopaside II Reduces Endothelial Cell Migration and Tubulogenesis and Induces Apoptosis." International Journal of Molecular Sciences 19, no. 3 (February 26, 2018): 653. http://dx.doi.org/10.3390/ijms19030653.

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Ecelbarger, Carolyn A., Chung-Lin Chou, Alanna J. Lee, Susan R. DiGiovanni, Joseph G. Verbalis, and Mark A. Knepper. "Escape from vasopressin-induced antidiuresis: role of vasopressin resistance of the collecting duct." American Journal of Physiology-Renal Physiology 274, no. 6 (June 1, 1998): F1161—F1166. http://dx.doi.org/10.1152/ajprenal.1998.274.6.f1161.

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Previously, we demonstrated that escape from vasopressin-induced antidiuresis (“vasopressin escape”) in rats is associated with a large, selective decrease in whole kidney expression of aquaporin-2, the vasopressin-regulated water channel. Here, we show that isolated perfused inner medullary collecting ducts (IMCDs) from vasopressin-escape rats {desamino-[d-arginine]vasopressin (DDAVP)/water-loaded} have dramatically reduced vasopressin-dependent osmotic water permeabilities [46% of control rats (DDAVP alone)], which coincides with a fall in inner medullary aquaporin-2 protein abundance as measured by immunoblotting in the opposite kidney. Furthermore, we demonstrate in IMCD suspensions that cAMP accumulation in response to DDAVP is substantially reduced in the vasopressin-escape rats both in the presence and absence of the phosphodiesterase inhibitor IBMX. By immunoblotting, we show that the abundance of two proteins important in cAMP generation: the stimulatory heterotrimeric G protein subunit Gsα and adenylyl cyclase type VI, do not change. We conclude that vasopressin escape is associated with relative vasopressin resistance of the collecting duct cells manifested by decreased intracellular cAMP levels. The decreased cAMP levels can contribute to the demonstrated decrease in collecting duct water permeability in two ways: 1) by causing a decrease in aquaporin-2 expression and 2) by limiting the acute action of vasopressin to increase collecting duct water permeability.

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Rossino, Giacomo, Marta Rui, Luca Pozzetti, Dirk Schepmann, Bernhard Wünsch, Daniele Zampieri, Giorgia Pellavio, et al. "Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)." International Journal of Molecular Sciences 21, no. 20 (October 18, 2020): 7708. http://dx.doi.org/10.3390/ijms21207708.

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Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the affinity of small molecules against S1R. The docking method was validated by comparing the computational calculated Ki values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding affinity. The druggability profile of the new compounds, with particular reference to the ability to cross the blood–brain barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-d-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,1’-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one (12) performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good affinity against both S1R and NMDA receptor, good selectivity over S2R and favorable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant effects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent.

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Qiu, Quan-Sheng, Ze-Zhou Wang, Nang Zhang, Qi-Gui Cai, and Rong-Xi Jiang. "Aquaporins in the plasma membrane of leaf callus protoplasts of Actinidia deliciosa var. deliciosa cv. Hayward." Functional Plant Biology 27, no. 1 (2000): 71. http://dx.doi.org/10.1071/pp99033.

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The water transport activity of Actinidia deliciosa protoplasts was determined using a cell imaging system. Results showed that the protoplast volume increased swiftly when placed in a hypoton-ic medium, and also increased with an increase in medium osmotic gradients. The osmotic water permeability coefficient (Pf) values were 0.118 × 10–3, 0.121 × 10–3, and 0.133 × 10–3 cm s–1 when the osmotic gradients were 75, 100, and 125 mosmol, respectively. The water transport activity of protoplas-ts could be inhibited by HgCl2 and stimulated by amphotericin B. Moreover, ZnCl2 and ZnSO4 had a significant inhibitory effect on the water transport activity of the protoplasts. Our results indicate that the Actinidia deliciosa protoplasts had properties typical of aquaporins, suggesting that aquaporins were present at the plasma membrane.

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Baltzer, Sandrine, Timur Bulatov, Christopher Schmied, Andreas Krämer, Benedict-Tilman Berger, Andreas Oder, Ryan Walker-Gray, et al. "Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells." International Journal of Molecular Sciences 23, no. 2 (January 11, 2022): 763. http://dx.doi.org/10.3390/ijms23020763.

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The cAMP-dependent aquaporin-2 (AQP2) redistribution from intracellular vesicles into the plasma membrane of renal collecting duct principal cells induces water reabsorption and fine-tunes body water homeostasis. However, the mechanisms controlling the localization of AQP2 are not understood in detail. Using immortalized mouse medullary collecting duct (MCD4) and primary rat inner medullary collecting duct (IMCD) cells as model systems, we here discovered a key regulatory role of Aurora kinase A (AURKA) in the control of AQP2. The AURKA-selective inhibitor Aurora-A inhibitor I and novel derivatives as well as a structurally different inhibitor, Alisertib, prevented the cAMP-induced redistribution of AQP2. Aurora-A inhibitor I led to a depolymerization of actin stress fibers, which serve as tracks for the translocation of AQP2-bearing vesicles to the plasma membrane. The phosphorylation of cofilin-1 (CFL1) inactivates the actin-depolymerizing function of CFL1. Aurora-A inhibitor I decreased the CFL1 phosphorylation, accounting for the removal of the actin stress fibers and the inhibition of the redistribution of AQP2. Surprisingly, Alisertib caused an increase in actin stress fibers and did not affect CFL1 phosphorylation, indicating that AURKA exerts its control over AQP2 through different mechanisms. An involvement of AURKA and CFL1 in the control of the localization of AQP2 was hitherto unknown.

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Zhang, Qiang, Lejun Lin, Weilong Li, Guowei Lu, and Xinna Li. "MiR-223 inhibitor suppresses proliferation and induces apoptosis of thyroid cancer cells by down-regulating aquaporin-1." Journal of Receptors and Signal Transduction 39, no. 2 (March 4, 2019): 146–53. http://dx.doi.org/10.1080/10799893.2019.1638403.

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Luo, Gang-Yue, Li Sun, and Timon Cheng-Yi Liu. "Aquaporin-1-Mediated Effects of Low Level He-Ne Laser Irradiation on Human Erythrocytes." International Journal of Photoenergy 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/275209.

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The role of membrane aquaporin-1 (APQ-1) in the photobiomodulation (PBM) on erythrocyte deformability will be studied in this paper with human dehydrated erythrocytes as echinocytic shape alterations lead to decreased cellular deformability. Human dehydrated erythrocytes were irradiated with low intensity He-Ne laser irradiation (LHNL) at 0.9, 1.8, 2.7, and 4.4 mW/cm2for 5, 15, and 30 min, respectively, and APQ-1 inhibitor, 0.2 μmol/L HgCl2, was used to study the role of APQ-1 in mediating PBM with LHNL at 4.4 mW/cm2for 5 min. Comprehensive morphological parameters of an intact cell such as contact area, perimeter, roundness and erythrocyte elongation index (EEI) were measured to characterize erythrocyte deformability with fast micro multi-channel spectrophotometer. It was observed that the dosage of LHNL improvement of the morphological parameters of dehydrated erythrocytes was morphological-parameter-dependent, but the Bunsen-Roscoe rule did not hold for roundness. The LHNL at 4.4 mW/cm2for 5 min significantly improved the contact area (P<0.05) and EEI (P<0.05) of the dehydrated erythrocytes, but the improvement was significantly inhibited by 0.2 μmol/L HgCl2(P<0.05). It was concluded that AQP-1 might mediate the effects of LHNL on erythrocyte deformability, which supports the membranotropic mechanism of PBM.

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Li, Chunling, Weidong Wang, Christopher J. Rivard, Miguel A. Lanaspa, Sandra Summer, and Robert W. Schrier. "Molecular mechanisms of angiotensin II stimulation on aquaporin-2 expression and trafficking." American Journal of Physiology-Renal Physiology 300, no. 5 (May 2011): F1255—F1261. http://dx.doi.org/10.1152/ajprenal.00469.2010.

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ANG II plays a major role in renal water and sodium regulation. In the immortalized mouse renal collecting duct principal cells (mpkCCDcl4) cell line, we treated cells with ANG II and examined aquaporin-2 (AQP2) protein expression, trafficking, and mRNA levels, by immunoblotting, immunofluorescence, and RT-PCR. After 24-h incubation, ANG II-induced AQP2 protein expression was observed at the concentration of 10−10 M and increased in a dose-dependent manner. ANG II (10−7 M) increased AQP2 protein expression and mRNA levels at 0.5, 1, 2, 6, and 24 h. Immunofluorescence studies showed that ANG II increased the apical membrane targeting of AQP2 from 30 min to 6 h. Next, the signaling pathways underlying the ANG II-induced AQP2 expression were investigated. The PKC inhibitor Ro 31–8220 (5 × 10−6 M) and the PKA inhibitor H89 (10−5 M) blocked ANG II-induced AQP2 expression, respectively. Calmodulin inhibitor W-7 markedly reduced ANG II- and/or dDAVP-stimulated AQP2 expression. ANG II (10−9 M) and/or dDAVP (10−10 M) stimulated AQP2 protein levels and cAMP accumulation, which was completely blocked by pretreatment with the vasopressin V2 receptor (V2R) antagonist SR121463B (10−8 M). Pretreatment with the angiotensin AT1 receptor (AT1R) antagonist losartan (3 × 10−6 M) blocked ANG II (10−9 M)-stimulated AQP2 protein expression and cAMP accumulation, and partially blocked dDAVP (10−10 M)- and dDAVP+ANG II-induced AQP2 protein expression and cAMP accumulation. In conclusion, ANG II regulates AQP2 protein, trafficking, and gene expression in renal collecting duct principal cells. ANG II-induced AQP2 expression involves cAMP, PKC, PKA, and calmodulin signaling pathways via V2 and AT1 receptors.

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Journal articles on the topic 'Aquaporin 1 inhibitors'

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