Molecular mechanisms regulating aquaporin-2 in kidney collecting duct

Jung, Hyun Jun; Kwon, Tae Hwan

doi:10.1152/ajprenal.00485.2016

Cited by 96 publications

(91 citation statements)

References 158 publications

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“…Upon ADH binding, V2R stimulates a cascade of events, mainly cyclic AMP-dependent ones, leading to the phosphorylation of AQP2, the water channel exclusively expressed by the principal cells of the CD. Phosphorylation at canonical serine sites of the C-terminal tail of the protein allows AQP2 trafficking towards the apical membrane of the principal cells [36] ( Fig. 2 ).…”

Section: Pathophysiology Of Urine Concentration and Dilutionmentioning

confidence: 99%

The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

et al. 2017

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Background: The ciliopathies are a growing number of disorders caused by mutations in genes involved in the function of the primary cilium. Bardet-Biedl syndrome (BBS) belongs to this group of disorders. In this setting, kidney dysfunction is highly variable, and urine concentrating defect, a common feature of multiple ciliopathies, has been described as the most frequent defect. Here we review the mechanism of urine concentration and describe the possible mechanism underling this defect in ciliopathies and especially BBS, based on the current body of literature. Summary: Active Na⁺ absorption along the thick ascending limb of the loop of Henle (TAL) is critical for generating the corticomedullary osmotic gradient, and the countercurrent anatomical arrangement of the 2 branches of the loop of Henle enhances this gradient. The vasa recta, paralleling the loop of Henle, operate into the countercurrent mechanism, minimizing washout of solutes from the interstitium. Final water reabsorption is mediated by the aquaporin 2 (AQP2) water channels along the distal nephron, and it is under hormonal control. Several studies demonstrated that hyposthenuria in BBS patients relies on kidney resistance to desmopressin, suggesting a renal origin. We recently showed that the majority of hyposthenuric BBS patients have also a defect regarding maximal urine dilution. Independent studies showed that BBS10 deficiency caused AQP2 mistrafficking in vitro; accordingly, we demonstrated impaired urinary AQP2 excretion in BBS patients with combined concentrating and diluting defect. Whether receptor signaling pathways or downstream events cause AQP2 deregulation is still unclear. In addition, reduced urinary uromodulin excretion in BBS patients opens the possibility that TAL dysfunction may also play a pathogenic role. Key Message: Impaired water handling in BBS is associated with AQP2 mistrafficking. The potential role of additional factors, such as the dissipation of the medullary osmotic gradient due to TAL dysfunction and/or structural anomalies, remains to be elucidated.

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Section: Pathophysiology Of Urine Concentration and Dilutionmentioning

confidence: 99%

The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

et al. 2017

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“…, ; Kwon et al . ; Noda, ; Jung & Kwon, ). This increases water permeability in kidney collecting ducts, and effectively conserves water.…”

Section: Introductionmentioning

confidence: 99%

“…Aquaporin 2 (AQP2) is crucial for regulation of water balance by the kidney. Under basal conditions, cytosolic AQP2 constitutively traffics to the plasma membrane (Gustafson et al 2000;Zhang et al 2002;Lu et al 2004), and once stimulated by VP, AQP2 phosphorylation is modified (Fushimi et al 1997;Katsura et al 1997), and the equilibrium between endocytosis and exocytosis changes to favour an increase of AQP2 membrane accumulation (Moeller et al 2010(Moeller et al , 2012Kwon et al 2013;Noda, 2014;Jung & Kwon, 2016). This increases water permeability in kidney collecting ducts, and effectively conserves water.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation

Cheung

Terlouw

Janssen

et al. 2018

The Journal of Physiology

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Key points Aquaporin‐2 (AQP2) is crucial for water homeostasis, and vasopressin (VP) induces AQP2 membrane trafficking by increasing intracellular cAMP, activating PKA and causing phosphorylation of AQP2 at serine 256, 264 and 269 residues and dephosphorylation of serine 261 residue on the AQP2 C‐terminus. It is thought that serine 256 is the master regulator of AQP2 trafficking, and its phosphorylation has to precede the change of phosphorylation state of other serine residues. We found that Src inhibition causes serine 256‐independent AQP2 membrane trafficking and induces phosphorylation of serine 269 independently of serine 256. This targeted phosphorylation of serine 269 is important for Src inhibition‐induced AQP2 membrane accumulation; without serine 269, Src inhibition exerts no effect on AQP2 trafficking. This result helps us better understand the independent pathways that can target different AQP2 residues, and design new strategies to induce or sustain AQP2 membrane expression when VP signalling is defective. Abstract Aquaporin‐2 (AQP2) is essential for water homeostasis. Upon stimulation by vasopressin, AQP2 is phosphorylated at serine 256 (S256), S264 and S269, and dephosphorylated at S261. It is thought that S256 is the master regulator of AQP2 trafficking and membrane accumulation, and that its phosphorylation has to precede phosphorylation of other serine residues. In this study, we found that VP reduces Src kinase phosphorylation: by suppressing Src using the inhibitor dasatinib and siRNA, we could increase AQP2 membrane accumulation in cultured AQP2‐expressing cells and in kidney collecting duct principal cells. Src inhibition increased exocytosis and inhibited clathrin‐mediated endocytosis of AQP2, but exerted its effect in a cAMP, PKA and S256 phosphorylation (pS256)‐independent manner. Despite the lack of S256 phosphorylation, dasatinib increased phosphorylation of S269, even in S256A mutant cells in which S256 phosphorylation cannot occur. To confirm the importance of pS269 in AQP2 re‐distribution, we expressed an AQP2 S269A mutant in LLC‐PK1 cells, and found that dasatinib no longer induced AQP2 membrane accumulation. In conclusion, Src inhibition causes phosphorylation of S269 independently of pS256, and induces AQP2 membrane accumulation by inhibiting clathrin‐mediated endocytosis and increasing exocytosis. We conclude that S269 can be phosphorylated without pS256, and pS269 alone is important for AQP2 apical membrane accumulation under some conditions. These data increase our understanding of the independent pathways that can phosphorylate different residues in the AQP2 C‐terminus, and suggest new strategies to target distinct AQP2 serine residues to induce membrane expression of this water channel when VP signalling is defective.

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“…These are made up by approximately 270 amino acid residues, and are organized into the membrane as homotetrameres; each monomer has an independent water pore. There are13 aquaporins (aquaporin 0 to 12) subdivided into three subfamilies: aquaporin subfamily (AQP0,1,2,4,5,6,8,10), aquaglyceroporin subfamily (AQP 3, 7, 9) and superaquaporin subfamily [5,6,7,8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Upon stimulation it moves into the cell membrane where it functions as a water channel. The most important stimulation factor is vasopressin, which translocates AQP2 through adenyl cyclase (AC), elevation of cAMP levels and activation of the protein kinase A (PKA) intracellular signaling pathway [7,9].…”

Section: Introductionmentioning

confidence: 99%

Aquaporin 2 Expression in Human Fetal Kidney Development

Ráduly

Dénes

et al. 2018

Acta Medica Marisiensis

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Introduction: The metanephrogenic zone, renal cortex and renal pyramids develop into their final form by week 13. The metanephric kidney produces large quantities of diluted urine in order to maintain volumes of amniotic fluid. Aquaporins are transmembrane protein channels that enable water transport through biological membranes. Aquaporin 2 (AQP2) is a water channel found in the supranuclear region and apical area of the cell membrane of the kidneys collecting tubule cells. Its main function is reabsorption of water through vasopressin stimulation. Materials and methods: Immunohistochemistry was used to study fetal renal tissue of 34 post-mortem fetuses of 9 weeks to 24 weeks gestational age. Results: AQP2 expression is present in connecting tubules and collecting tubules during the targeted time period. From week 9 to 12, the expression is cytoplasmic. From week 13 to 20 the enhancement of expression in the apical cell membrane occurs with the advancement of fetal age. At the end of the studied period, from week 21 to 24, both cytoplasmic and apical expression were observed. In animal studies AQP2 expression has an increasing trend during development. In contradiction with these results, other authors described low AQP2 levels in the human fetal kidney. Conclusions: This study helps to understand the amniotic fluid's homeostasis during pregnancy. In the beginning of the fetal period AQP2 protein is present in the cytoplasm of epithelial cells of the collecting duct and distal connecting duct. During the fetal period, AQP2 expression in collecting ducts becomes more enhanced in the apical membrane of the cells.

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Molecular mechanisms regulating aquaporin-2 in kidney collecting duct

Cited by 96 publications

References 158 publications

The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation

Aquaporin 2 Expression in Human Fetal Kidney Development

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