Congenital progressive hydronephrosis (
            <i>cph</i>
            ) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation

McDill, Bradley W.; Li, Song Zhe; Kovach, Paul A.; Ding, Li; Chen, Feng

doi:10.1073/pnas.0602087103

Cited by 127 publications

(105 citation statements)

References 27 publications

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“…[32][33][34] Mice with a mutation in S256-AQP2 (S256L) can not phosphorylate AQP2 at S256 because of the amino acid change and show reduced apical membrane accumulation (analyzed in outer medullary CD), resulting in NDI. 35 In contrast to AC6 Ϫ/Ϫ mice, these mice do not increase urine osmolality in BASIC RESEARCH www.jasn.org response to dDAVP. We propose that the ability of AC6 Ϫ/Ϫ mice to concentrate their urine is caused in part by the maintenance of phosphorylation and apical redistribution of AQP2 in renal cortex and outer medulla, where the majority of the osmotic water reabsorption occurs.…”

Section: Discussionmentioning

confidence: 99%

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Rieg

Tang²,

Murray³

et al. 2010

Journal of the American Society of Nephrology

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Arginine vasopressin (AVP) enhances water reabsorption in the renal collecting duct by vasopressin V 2 receptor (V 2 R)-mediated activation of adenylyl cyclase (AC), cAMP-promoted phosphorylation of aquaporin-2 (AQP2), and increased abundance of AQP2 on the apical membrane. Multiple isoforms of adenylate cyclase exist, and the roles of individual AC isoforms in water homeostasis are not well understood. Here, we found that levels of AC6 mRNA, the most highly expressed AC isoform in the inner medulla, inversely correlate with fluid intake. Moreover, mice lacking AC6 had lower levels of inner medullary cAMP, reduced abundance of phosphorylated AQP2 (at both serine-256 and serine-269), and lower urine osmolality than wild-type mice. Water deprivation or administration of the V 2 R agonist dDAVP did not increase urine osmolality of AC6-deficient mice to the levels of wild-type mice. Furthermore, AC6-deficient mice lacked dDAVP-promoted inner medullary cAMP formation and phosphorylation of serine-269 and had attenuated increases in both phosphorylation of serine-256 and apical membrane AQP2 trafficking. In summary, AC6 expression determines inner medullary cAMP formation and AQP2 phosphorylation and trafficking, the absence of which causes nephrogenic diabetes insipidus. The anti-diuretic hormone arginine-vasopressin (AVP) is the primary regulator of water reabsorption in the renal collecting duct (CD) and is critically involved in the regulation of water balance and maintenance of plasma osmolality. 1 AVP acts on the CD through the G s protein-coupled vasopressin V 2 receptor (V 2 R) to stimulate adenylyl cyclase (AC) and thus the synthesis of cAMP. 2 cAMP activates protein kinase A (PKA), which phosphorylates the water channel aquaporin-2 (AQP2) in its COOH-terminal tail on serine residue 256 (S256), thereby resulting in apical plasma membrane accumulation of AQP2. [3][4][5][6] In addition, cAMP-independent activation of AQP2 has been reported, which may involve V 2 R action of phosphoinositide-specific phospholipase C. 7 Other non-PKA-targeted AQP2 phosphorylation sites include S261, S264, and S269. 8 Phosphorylation of AQP2 at S264 and S269 requires prior phosphorylation of S256. 9 Immunohistochemistry showed that pS269-AQP2 localizes exclusively in the apical plasma

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Section: Discussionmentioning

confidence: 99%

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Rieg

Tang²,

Murray³

et al. 2010

Journal of the American Society of Nephrology

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“…After small increases in plasma osmolality, AVP is released by the posterior pituitary gland and binds to the type II AVP receptor (V2R) in the CD, leading to activation of adenylyl cyclase, increased intracellular cAMP levels, increased intracellular calcium, and activation of PKA. Numerous studies, in both cell culture and animal models, suggest that PKA phosphorylation of serine 256 (S256) in the COOH tail of AQP2 plays a critical role in its apical trafficking (2)(3)(4)(5). In addition to S256, we have discovered recently that AQP2 is further phosphorylated on residues S261, S264, and S269 in the COOH tail in response to AVP stimulation (6,7).…”

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confidence: 95%

Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin

Fenton

Moeller²,

Hoffert³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

106

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By phosphoproteome analysis, we identified a phosphorylation site, serine 264 (pS264), in the COOH terminus of the vasopressinregulated water channel, aquaporin-2 (AQP2). In this study, we examined the regulation of AQP2 phosphorylated at serine 264 (pS264 -AQP2) by vasopressin, using a phospho-specific antibody (anti-pS264). Immunohistochemical analysis showed pS264 -AQP2 labeling of inner medullary collecting duct (IMCD) from control mice, whereas AQP2 knockout mice showed a complete absence of labeling. In rat and mouse, pS264 -AQP2 was present throughout the collecting duct system, from the connecting tubule to the terminal IMCD. Immunogold electron microscopy, combined with double-labeling confocal immunofluorescence microscopy with organelle-specific markers, determined that the majority of pS264 resides in compartments associated with the plasma membrane and early endocytic pathways. In Brattleboro rats treated with [deamino-Cys-1, D-Arg-8]vasopressin (dDAVP), the abundance of pS264 -AQP2 increased 4-fold over controls. Additionally, dDAVP treatment resulted in a time-dependent change in the distribution of pS264 from predominantly intracellular vesicles, to both the basolateral and apical plasma membranes. Sixty minutes after dDAVP exposure, a proportion of pS264 -AQP2 was observed in clathrin-coated vesicles, early endosomal compartments, and recycling compartments, but not lysosomes. Overall, our results are consistent with a dynamic effect of AVP on the phosphorylation and subcellular distribution of AQP2.concentrating mechanism ͉ immunohistochemistry ͉ kidney ͉ trafficking T he maintenance of body water homeostasis depends on the fine control of renal water excretion, a process that is regulated by the antidiuretic hormone arginine vasopressin (AVP). An essential step in the action of AVP is the trafficking of intracellular vesicles containing the AVP-sensitive water channel aquaporin-2 (AQP2) to the plasma membrane of kidney collecting duct (CD) principal cells, a process that ultimately increases osmotically driven water reabsorption from the CD lumen and the production of concentrated urine (1). After small increases in plasma osmolality, AVP is released by the posterior pituitary gland and binds to the type II AVP receptor (V2R) in the CD, leading to activation of adenylyl cyclase, increased intracellular cAMP levels, increased intracellular calcium, and activation of PKA. Numerous studies, in both cell culture and animal models, suggest that PKA phosphorylation of serine 256 (S256) in the COOH tail of AQP2 plays a critical role in its apical trafficking (2-5). In addition to S256, we have discovered recently that AQP2 is further phosphorylated on residues S261, S264, and S269 in the COOH tail in response to AVP stimulation (6, 7).In this study, we examined the regulation of AQP2 phosphorylated at serine 264 (pS264-AQP2) by AVP in a number of in vivo models by using a phospho-specific antibody. Our findings demonstrated that pS264-AQP2 abundance is regulated acutely by AVP and that pS264-AQP2 app...

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“…Polyuria has the potential to eventually overwhelm the pyeloureteral peristaltic machinery for urine transfer, leading to hydronephrosis and renal failure. [17][18][19] Because the mice with hydronephrosis had various degrees of erosion of the renal parenchyma starting from the inner medulla, we analyzed these mice separately and focused mostly on the cortex, where structures were still relatively intact and recognizable. We found that the percentage of ATPase + ICs in the cortex was similar between mutants with hydronephrosis (46.51% 64.38%) and mutants without hydronephrosis (46.91% 65.49%) (P=0.68).…”

Section: Deletion Of Adam10 In Ub Derivatives Led To Polyuria and Hydmentioning

confidence: 99%

“…We thus suspect that functional defects in handling urine transport or polyuria may be the primary cause of hydronephrosis, although other causes cannot be excluded at this point. [17][18][19] Absence of Adam10 in Collecting Duct Progenitor Cells Results in an Altered Ratio of PCs to ICs To distinguish the two main cell types in the collecting duct, namely the PCs and the ICs, we performed immunofluorescence staining on kidney sections with Aqp2 (a PC marker), and ATPase (an IC marker) (Figure 2, A-H). The proportion of ATPase + ICs was significantly higher in the mutants than in the controls (Figure 2, A-F and I).…”

Section: Deletion Of Adam10 In Ub Derivatives Led To Polyuria and Hydmentioning

confidence: 99%

Adam10 Mediates the Choice between Principal Cells and Intercalated Cells in the Kidney

Guo

Wang²,

Tripathi³

et al. 2015

Journal of the American Society of Nephrology

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A disintegrin and metalloproteinase domain 10 (Adam10), a member of the ADAM family of cell membrane-anchored proteins, has been linked to the regulation of the Notch, EGF, E-cadherin, and other signaling pathways. However, it is unclear what role Adam10 has in the kidney in vivo. In this study, we showed that Adam10 deficiency in ureteric bud (UB) derivatives leads to a decrease in urinary concentrating ability, polyuria, and hydronephrosis in mice. Furthermore, Adam10 deficiency led to a reduction in the percentage of aquaporin 2 (Aqp2) + principal cells (PCs) in the collecting ducts that was accompanied by a proportional increase in the percentage of intercalated cells (ICs). This increase was more prominent in type A ICs than in type B ICs. Foxi1, a transcription factor important for the differentiation of ICs, was upregulated in the Adam10 mutants. The observed reduction of Notch activity in Adam10 mutant collecting duct epithelium and the similar reduction of PC/IC ratios in the collecting ducts in mice deficient for mindbomb E3 ubiquitin protein ligase 1, a key regulator of the Notch and Wnt/receptor-like tyrosine kinase signaling pathways, suggest that Adam10 regulates cell fate determination through the activation of Notch signaling, probably through the regulation of Foxi1 expression. However, phenotypic differences between the Adam10 mutants, the Mib1 mutants, and the Foxi1 mutants suggest that the functions of Adam10 in determining the fate of collecting duct cells are more complex than those of a simple upstream factor in a linear pathway involving Notch and Foxi1.

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Congenital progressive hydronephrosis ( cph ) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation

Cited by 127 publications

References 27 publications

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin

Adam10 Mediates the Choice between Principal Cells and Intercalated Cells in the Kidney

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