Expression and distribution of aquaporin of collecting duct are regulated by vasopressin V2 receptor in rat kidney.

Hayashi, Matsuhiko; Sasaki, Sei; Tsuganezawa, Hirohiko; Monkawa, Toshiaki; Kitajima, Waichi; Konishi, Kohnosuke; Fushimi, Kiyohide; Marumo, Fumiaki; Saruta, Takao

doi:10.1172/jci117525

Cited by 168 publications

(101 citation statements)

References 21 publications

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“…4B). AQP2 is phosphorylated by PKA in response to DDAVP (Ausiello et al, 1987;Hayashi et al, 1994). The observed lack of p-AQP2 could be due to alterations in PKA expression and/or activity in the -/-mice.…”

Section: Resultsmentioning

confidence: 96%

“…Activation of the V 2 R causes stimulation of adenylyl cyclase via the G protein G S , leading to elevation of cAMP and subsequent activation of protein kinase A (PKA) (Wade et al, 1981). PKA phosphorylates AQP2 at serine reside 256, resulting in enhanced accumulation of AQP2-bearing vesicles in the plasma membrane where AQP2 is inserted by an exocytosislike process (Ausiello et al, 1987;Hayashi et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Loss of calcineurin Aα results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus

Gooch

Guler

Barnes

et al. 2006

Journal of Cell Science

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The serine/threonine phosphatase calcineurin is an important signaling molecule involved in kidney development and function. One potential target of calcineurin action is the water channel aquaporin 2 (AQP2). In this study, we examined the effect of loss of calcineurin Aα (CnAα) on AQP2 function in vivo. CnAα null mice were found to have defective post-natal urine-concentrating ability and an impaired urine-concentrating response to vasopressin. Expression of AQP2 is normal but, paradoxically, vasopressin-mediated phosphorylation of the channel is decreased compared with wild-type littermates and there is no accumulation of AQP2 in the apical membrane. Calcineurin protein and activity was found in innermedullary collecting duct vesicles, and loss of calcineurin expression and activity was associated with a loss of AQP2 in the vesicle fraction. As such, the lack of vasopressin-mediated phosphorylation of AQP2 might be the result of a defect in normal trafficking of AQP2 to apical-targeted vesicles. Likewise, treatment of wild-type mice with cyclosporin A to inhibit calcineurin produces a similarly impaired urine-concentrating response to vasopressin and alterations in AQP2 phosphorylation and trafficking. These experiments demonstrate that, CnAα is required for normal intracellular trafficking of AQP2 and loss of calcineurin protein or activity disrupts AQP2 function.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Loss of calcineurin Aα results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus

Gooch

Guler

Barnes

et al. 2006

Journal of Cell Science

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“…2B). AQP2 transcript up-regulation is known to occur with dehydration (27,28). To confirm that AQP2 in kidneys of mutant mice contained the engineered mutations, the full-length AQP2 coding sequence was RT-PCR amplified from wild-type and mutant mice.…”

Section: Resultsmentioning

confidence: 99%

Neonatal Mortality in an Aquaporin-2 Knock-in Mouse Model of Recessive Nephrogenic Diabetes Insipidus

Yang

Gillespie

Carlson

et al. 2001

Journal of Biological Chemistry

154

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Hereditary non-X-linked nephrogenic diabetes insipidus (NDI) is caused by mutations in the aquaporin-2 (AQP2) water channel. In transfected cells, the human disease-causing mutant AQP2-T126M is retained at the endoplasmic reticulum (ER) where it is functional and targetable to the plasma membrane with chemical chaperones. A mouse knock-in model of NDI was generated by targeted gene replacement using a Cre-loxP strategy. Along with T126M, mutations H122S, N124S, and A125T were introduced to preserve the consensus sequence for N-linked glycosylation found in human AQP2. Breeding of heterozygous mice yielded the expected Mendelian distribution with 26 homozygous mutant offspring of 99 live births. The mutant mice appeared normal at 2-3 days after birth but failed to thrive and generally died by day 6 if not given supplemental fluid. Urine/serum analysis showed a urinary concentrating defect with serum hyperosmolality and low urine osmolality that was not increased by a V2 vasopressin agonist. Northern blot analysis showed up-regulated AQP2-T126M transcripts of identical size to wild-type AQP2. Immunoblots showed complex glycosylation of wild-type AQP2 but mainly endoglycosidase H-sensitive core glycosylation of AQP2-T126M indicating ER-retention. Biochemical analysis revealed that the AQP2-T126M protein was resistant to detergent solubilization. Kidneys from mutant mice showed collecting duct dilatation, papillary atrophy, and unexpectedly, some plasma membrane AQP2 staining. The severe phenotype of the AQP2 mutant mice compared with that of mice lacking kidney water channels AQP1, AQP3, and AQP4 indicates a critical role for AQP2 in neonatal renal function in mice. Our results establish a mouse model of human autosomal NDI and provide the first in vivo biochemical data on a diseasecausing AQP2 mutant.The formation of concentrated urine by the kidney requires high osmotic water permeability across the collecting duct epithelium. Collecting duct epithelial cells express aquaporin water channels AQP2, 1 AQP3, and AQP4 (1-4). AQP2 is the vasopressin (antidiuretic hormone)-regulated water channel (5, 6). Vasopressin induces the fusion of intracellular vesicles containing AQP2 with the apical plasma membrane resulting in increased water permeability (7-9). AQP2 is of considerable clinical importance in fluid and electrolyte balance. Mutations in human AQP2 cause hereditary non-X-linked nephrogenic diabetes insipidus (10 -13). Down-regulation of AQP2 expression occurs in several forms of acquired NDI (14), and AQP2 up-regulation is important in the pathophysiology of fluidretaining states such as congestive heart failure (15, 16). AQP3 and AQP4 are expressed constitutively at the basolateral membrane of collecting duct epithelial cells, with AQP3 mainly in cortical collecting duct and AQP4 in inner medullary collecting duct. Transgenic mice lacking AQP3 have low water permeability in cortical collecting duct and manifest NDI with marked polyuria and decreased urine osmolality (17). In contrast, mice lacking AQP4 show onl...

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“…The staining pattern of Clint in the collecting duct is reminiscent to that of aquaporin 2 and the V-ATPase (our unpublished data). Aquaporin 2 is localized in apical vesicles and in the apical plasma membrane (Hayashi et al, 1994;Sasaki et al, 1994). In type A intercalated cells of the collecting duct the V-ATPase also localizes to apical vesicles and to the apical plasma membrane (Brown and Breton, 2000).…”

Section: Discussionmentioning

confidence: 99%

Clint: A Novel Clathrin-binding ENTH-Domain Protein at the Golgi

Kalthoff¹,

Groos

Kohl³

et al. 2002

MBoC

118

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We have characterized a novel clathrin-binding 68-kDa epsin N-terminal homology domain (ENTH-domain) protein that we name clathrin interacting protein localized in the trans-Golgi region (Clint). It localizes predominantly to the Golgi region of epithelial cells as well as to more peripheral vesicular structures. Clint colocalizes with AP-1 and clathrin only in the perinuclear area. Recombinantly expressed Clint interacts directly with the ␥-appendage domain of AP-1, with the clathrin N-terminal domain through the peptide motif 423 LFDLM, with the ␥-adaptin ear homology domain of Golgi-localizing, ␥-adaptin ear homology domain 2, with the appendage domain of ␤2-adaptin and to a lesser extent with the appendage domain of ␣-adaptin. Moreover, the Clint ENTH-domain asssociates with phosphoinositide-containing liposomes. A significant amount of Clint copurifies with rat liver clathrin-coated vesicles. In rat kidney it is preferentially expressed in the apical region of epithelial cells that line the collecting duct. Clathrin and Clint also colocalize in the apical region of enterocytes along the villi of the small intestine. Apart from the ENTH-domain Clint has no similarities with the epsins AP180/CALM or Hip1/1R. A notable feature of Clint is a carboxyl-terminal methionine-rich domain (Met 427 -Met 605 ), which contains Ͼ17% methionine. Our results suggest that Clint might participate in the formation of clathrincoated vesicles at the level of the trans-Golgi network and remains associated with the vesicles longer than clathrin and adaptors.

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Expression and distribution of aquaporin of collecting duct are regulated by vasopressin V2 receptor in rat kidney.

Cited by 168 publications

References 21 publications

Loss of calcineurin Aα results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus

Loss of calcineurin Aα results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus

Neonatal Mortality in an Aquaporin-2 Knock-in Mouse Model of Recessive Nephrogenic Diabetes Insipidus

Clint: A Novel Clathrin-binding ENTH-Domain Protein at the Golgi

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