scholarly journals Molecular Mechanisms and Drug Development in Aquaporin Water Channel Diseases: Water Channel Aquaporin-2 of Kidney Collecting Duct Cells

2004 ◽  
Vol 96 (3) ◽  
pp. 255-259 ◽  
Author(s):  
Kuniaki Takata ◽  
Yuki Tajika ◽  
Toshiyuki Matsuzaki ◽  
Takeo Aoki ◽  
Takeshi Suzuki ◽  
...  
Keyword(s):  
Drug Development ◽  
Molecular Mechanisms ◽  
Collecting Duct ◽  
Water Channel ◽  
Kidney Collecting Duct ◽  
Aquaporin 2 ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Aquaporin Water Channel

scholarly journals Lixivaptan, a New Generation Diuretic, Counteracts Vasopressin-Induced Aquaporin-2 Trafficking and Function in Renal Collecting Duct Cells

2019 ◽  
Vol 21 (1) ◽  
pp. 183
Author(s):  
Annarita Di Mise ◽  
Maria Venneri ◽  
Marianna Ranieri ◽  
Mariangela Centrone ◽  
Lorenzo Pellegrini ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Plasma Osmolality ◽  
Kinetic Measurements ◽  
Aquaporin 2 ◽  
Plasma Vasopressin ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Renal Collecting Duct ◽  
New Generation

Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic drug would be preferable over a conventional diuretic. The clinical efficacy of vaptans is in principle due to impaired vasopressin-regulated water reabsorption via the water channel aquaporin-2 (AQP2). Here, the effect of lixivaptan—a novel selective V2R antagonist—on the vasopressin-cAMP/PKA signaling cascade was investigated in mouse renal collecting duct cells expressing AQP2 (MCD4) and the human V2R. Compared to tolvaptan—a selective V2R antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia—lixivaptan has been predicted to be less likely to cause liver injury. In MCD4 cells, clinically relevant concentrations of lixivaptan (100 nM for 1 h) prevented dDAVP-induced increase of cytosolic cAMP levels and AQP2 phosphorylation at ser-256. Consistent with this finding, real-time fluorescence kinetic measurements demonstrated that lixivaptan prevented dDAVP-induced increase in osmotic water permeability. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of lixivaptan and suggest that lixivaptan has the potential to become a safe and effective therapy for the treatment of disorders characterized by high plasma vasopressin concentrations and water retention.

scholarly journals A Role for VAMP8/Endobrevin in Surface Deployment of the Water Channel Aquaporin 2

2009 ◽  
Vol 30 (1) ◽  
pp. 333-343 ◽  
Author(s):  
Cheng-Chun Wang ◽  
Chee Peng Ng ◽  
Hong Shi ◽  
Hwee Chien Liew ◽  
Ke Guo ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Protein ◽  
Collecting Duct ◽  
Water Channel ◽  
Snare Proteins ◽  
Snare Protein ◽  
Aquaporin 2 ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Intracellular Vesicles

ABSTRACT Vesicle-associated-membrane protein 8 (VAMP8) is highly expressed in the kidney, but the exact physiological and molecular functions executed by this v-SNARE protein in nephrons remain elusive. Here, we show that the depletion of VAMP8 in mice resulted in hydronephrosis. Furthermore, the level of the vasopressin-responsive water channel aquaporin 2 (AQP2) was increased by three- to fivefold in VAMP8-null mice. Forskolin and [desamino-Cys1, D-Arg8]-vasopressin (DDAVP)-induced AQP2 exocytosis was impaired in VAMP8-null collecting duct cells. VAMP8 was revealed to colocalize with AQP2 on intracellular vesicles and to interact with the plasma membrane t-SNARE proteins syntaxin4 and syntaxin3, suggesting that VAMP8 mediates the regulated fusion of AQP2-positive vesicles with the plasma membrane.

scholarly journals Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1060
Author(s):  
Marc Kaiser ◽  
Bayram Edemir
Keyword(s):  
Lithium Chloride ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Collecting Duct ◽  
Mrna Level ◽  
Inner Medullary Collecting Duct ◽  
Aquaporin 2 ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct

Lithium chloride (LiCl) is a widely used drug for the treatment of bipolar disorders, but as a side effect, 40% of the patients develop diabetes insipidus. LiCl affects the activity of the glycogen synthase kinase 3 (GSK3), and mice deficient for GSK3β showed a reduction in the urine concentration capability. The cellular and molecular mechanisms are not fully understood. We used primary cultured inner medullary collecting duct cells to analyze the underlying mechanisms. LiCl and the inhibitor of GSK3 (SB216763) induced a decrease in the aquaporin-2 (Aqp2) protein level. LiCl induced downregulation of Aqp2 mRNA expression while SB216763 had no effect and TWS119 led to increase in expression. The inhibition of the lysosomal activity with bafilomycin or chloroquine prevented both LiCl- and SB216763-mediated downregulation of Aqp2 protein expression. Bafilomycin and chloroquine induced the accumulation of Aqp2 in lysosomal structures, which was prevented in cells treated with dibutyryl cyclic adenosine monophosphate (dbcAMP), which led to phosphorylation and membrane localization of Aqp2. Downregulation of Aqp2 was also evident when LiCl was applied together with dbcAMP, and dbcAMP prevented the SB216763-induced downregulation. We showed that LiCl and SB216763 induce downregulation of Aqp2 via different mechanisms. While LiCl also affected the mRNA level, SB216763 induced lysosmal degradation. Specific GSK3β inhibition had an opposite effect, indicating a more complex regulatory mechanism.

scholarly journals Serine/threonine phosphatases and aquaporin-2 regulation in renal collecting duct

2017 ◽  
Vol 312 (1) ◽  
pp. F84-F95 ◽  
Author(s):  
Sophia M. LeMaire ◽  
Viswanathan Raghuram ◽  
Cameron R. Grady ◽  
Christina M. Pickering ◽  
Chung-Lin Chou ◽  
...  
Keyword(s):  
Large Scale ◽  
Collecting Duct ◽  
Water Channel ◽  
Aquaporin 2 ◽  
Proteomic Data ◽  
Large Scale Data ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Renal Collecting Duct ◽  
Scale Data

Phosphorylation of the aquaporin-2 (AQP2) water channel at four COOH-terminal serines plays a central role in the regulation of water permeability of the renal collecting duct. The level of phosphorylation at these sites is determined by a balance between phosphorylation by protein kinases and dephosphorylation by phosphatases. The phosphatases that dephosphorylate AQP2 have not been identified. Here, we use large-scale data integration techniques to identify serine-threonine phosphatases likely to interact with AQP2 in renal collecting duct principal cells. As a first step, we have created a comprehensive list of 38 S/T phosphatase catalytic subunits present in the mammalian genome. Then we used Bayes’ theorem to integrate available information from large-scale data sets from proteomic and transcriptomic studies to rank the known S/T phosphatases with regard to the likelihood that they interact with AQP2 in renal collecting duct cells. To broaden the analysis, we have generated new proteomic data (LC-MS/MS) identifying 4538 distinct proteins including 22 S/T phosphatases in cytoplasmic fractions from native inner medullary collecting duct cells from rats. The official gene symbols corresponding to the top-ranked phosphatases (common names in parentheses) were: Ppp1cb (PP1-β), Ppm1g (PP2C), Ppp1ca (PP1-α), Ppp3ca (PP2-B or calcineurin), Ppp2ca (PP2A-α), Ppp1cc (PP1-γ), Ppp2cb (PP2A-β), Ppp6c (PP6C), and Ppp5c (PP5). This ranking correlates well with results of prior reductionist studies of ion and water channels in renal collecting duct cells.

scholarly journals Molecular mechanisms regulating aquaporin-2 in kidney collecting duct

2016 ◽  
Vol 311 (6) ◽  
pp. F1318-F1328 ◽  
Author(s):  
Hyun Jun Jung ◽  
Tae-Hwan Kwon
Keyword(s):  
Molecular Mechanisms ◽  
Collecting Duct ◽  
Water Channel ◽  
Peptide Hormone ◽  
Urine Concentration ◽  
The Body ◽  
Apical Plasma Membrane ◽  
Kidney Collecting Duct ◽  
Aquaporin 2 ◽  
Aqp2 Gene

The kidney collecting duct is an important renal tubular segment for regulation of body water homeostasis and urine concentration. Water reabsorption in the collecting duct principal cells is controlled by vasopressin, a peptide hormone that induces the osmotic water transport across the collecting duct epithelia through regulation of water channel proteins aquaporin-2 (AQP2) and aquaporin-3 (AQP3). In particular, vasopressin induces both intracellular translocation of AQP2-bearing vesicles to the apical plasma membrane and transcription of the Aqp2 gene to increase AQP2 protein abundance. The signaling pathways, including AQP2 phosphorylation, RhoA phosphorylation, intracellular calcium mobilization, and actin depolymerization, play a key role in the translocation of AQP2. This review summarizes recent data demonstrating the regulation of AQP2 as the underlying molecular mechanism for the homeostasis of water balance in the body.

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