Mouse model of inducible nephrogenic diabetes insipidus produced by floxed aquaporin-2 gene deletion

2006 ◽  
Vol 291 (2) ◽  
pp. F465-F472 ◽  
Author(s):  
Baoxue Yang ◽  
Dan Zhao ◽  
Liman Qian ◽  
A. S. Verkman
Keyword(s):  
Mouse Model ◽  
Diabetes Insipidus ◽  
Urine Output ◽  
Nephrogenic Diabetes Insipidus ◽  
Gene Deletion ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Aquaporin 2 ◽  
Gene Excision ◽  
Aqp2 Gene

Transgenic mouse models of defective urinary concentrating ability produced by deletion of various membrane transport or receptor proteins, including aquaporin-2 (AQP2), are associated with neonatal mortality from polyuria. Here, we report an inducible mouse model of AQP2 gene deletion with severe polyuria in adult mice. LoxP sequences were inserted into introns 1 and 2 in the mouse AQP2 gene by homologous recombination in embryonic stem cells. Mating of germ-line AQP2-loxP mice with tamoxifen-inducible Cre-expressing mice produced offspring with inducible homozygous Cre-AQP2-loxP, which had a normal phenotype. Tamoxifen injections over 10 days resulted in AQP2 gene excision, with undetectable full-length AQP2 transcript in kidney and a >95% reduction in immunoreactive AQP2 protein. Urine osmolality decreased from ∼2,000 to <500 mosmol/kgH2O after 4–5 days, with urine output increasing from 2 to 25 ml/day. Urine osmolality did not increase after water deprivation. Interestingly, AQP3 protein expression in the collecting duct was increased by about fivefold after AQP2 gene excision. Mild renal damage was seen after 6 wk of polyuria, with collecting duct dilatation, yet normal creatinine clearance and serum chemistries. These results establish the first adult model of nephrogenic diabetes insipidus (NDI) caused by AQP2 deficiency, with daily urine output comparable to body weight, although remarkable preservation of renal function compared with non-inducible NDI models.

scholarly journals Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 Gene

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5803-5810 ◽  
Author(s):  
Hidetaka Suga ◽  
Hiroshi Nagasaki ◽  
Taka-aki Kondo ◽  
Yoshiki Okajima ◽  
Chizuko Suzuki ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Sendai Virus ◽  
Collecting Duct ◽  
Water Channel ◽  
Vector System ◽  
Aquaporin 2 ◽  
Chronic Disorder ◽  
Life Threatening ◽  
Aqp2 Gene

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/ΔF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/ΔF vector carrying a human AQP2 gene (AQP2-SeV/ΔF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

scholarly journals Nephrogenic diabetes insipidus in mice caused by deleting COOH-terminal tail of aquaporin-2

2007 ◽  
Vol 292 (5) ◽  
pp. F1334-F1344 ◽  
Author(s):  
Peijun P. Shi ◽  
Xiao R. Cao ◽  
Jing Qu ◽  
Ken A. Volk ◽  
Patricia Kirby ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Hormonal Regulation ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Collecting Duct ◽  
Phosphorylation Site ◽  
Water Channel ◽  
Urine Osmolality ◽  
Functional Expression ◽  
Aquaporin 2

In mammals, the hormonal regulation of water homeostasis is mediated by the aquaporin-2 water channel (Aqp2) of the collecting duct (CD). Vasopressin induces redistribution of Aqp2 from intracellular vesicles to the apical membrane of CD principal cells, accompanied by increased water permeability. Mutations of AQP2 gene in humans cause both recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. In this study, we generated a line of mice with the distal COOH-terminal tail of the Aqp2 deleted ( Aqp2Δ 230), including the protein kinase A phosphorylation site (S256), but still retaining the putative apical localization signal (221–229) at the COOH-terminal. Mice heterozygous for the truncation appear normal. Homozygotes are viable to adulthood, with reduced urine concentrating capacity, increased urine output, decreased urine osmolality, and increased daily water consumption. Desmopressin increased urine osmolality in wild-type mice but had no effect on Aqp2Δ 230/Δ 230 mice. Kidneys from affected mice showed CD and pelvis dilatation and papillary atrophy. By immunohistochemical and immunoblot analyses using antibody against the NH2-terminal region of the protein Aqp2Δ 230/Δ 230 mice had a markedly reduced protein abundance. Expression of the truncated protein in MDCK cells was consistent with a small amount of functional expression but no stimulation. Thus we have generated a mouse model of NDI that may be useful in studying the physiology and potential therapy of this disease.

scholarly journals Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus

2017 ◽  
Vol 313 (4) ◽  
pp. F914-F925 ◽  
Author(s):  
Yu Lin ◽  
Tiezheng Zhang ◽  
Pinning Feng ◽  
Miaojuan Qiu ◽  
Qiaojuan Liu ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Renin Inhibitor ◽  
Protein Abundance ◽  
Aquaporin 2 ◽  
Direct Renin Inhibitor ◽  
Collecting Ducts ◽  
Dry Food ◽  
Concentrating Defect

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.

scholarly journals Lithium-induced NDI: acetazolamide reduces polyuria but does not improve urine concentrating ability

2017 ◽  
Vol 313 (3) ◽  
pp. F669-F676 ◽  
Author(s):  
Theun de Groot ◽  
Joan Doornebal ◽  
Birgitte M. Christensen ◽  
Simone Cockx ◽  
Anne P. Sinke ◽  
...  
Keyword(s):  
Urine Output ◽  
Nephrogenic Diabetes Insipidus ◽  
Filtration Rate ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Systemic Blood Pressure ◽  
Systemic Blood ◽  
Urine Concentrating Ability ◽  
Concentrating Defect

Lithium is the mainstay treatment for patients with bipolar disorder, but it generally causes nephrogenic diabetes insipidus (NDI), a disorder in which the renal urine concentrating ability has become vasopressin insensitive. Li-NDI is caused by lithium uptake by collecting duct principal cells and downregulation of aquaporin-2 (AQP2) water channels, which are essential for water uptake from tubular urine. Recently, we found that the prophylactic administration of acetazolamide to mice effectively attenuated Li-NDI. To evaluate whether acetazolamide might benefit lithium-treated patients, we administered acetazolamide to mice with established Li-NDI and six patients with a lithium-induced urinary concentrating defect. In mice, acetazolamide partially reversed lithium-induced polyuria and increased urine osmolality, which, however, did not coincide with increased AQP2 abundances. In patients, acetazolamide led to the withdrawal of two patients from the study due to side effects. In the four remaining patients acetazolamide did not lead to clinically relevant changes in maximal urine osmolality. Urine output was also not affected, although none of these patients demonstrated overt lithium-induced polyuria. In three out of four patients, acetazolamide treatment increased serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). Strikingly, these three patients also showed a decrease in systemic blood pressure. All together, our data reveal that acetazolamide does not improve the urinary concentrating defect caused by lithium, but it lowers the GFR, likely explaining the reduced urine output in our mice and in a recently reported patient with lithium-induced polyuria. The reduced GFR in patients prone to chronic kidney disease development, however, warrants against application of acetazolamide in Li-NDI patients without long-term (pre)clinical studies.

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

2000 ◽  
Vol 276 (4) ◽  
pp. 2775-2779 ◽  
Author(s):  
Baoxue Yang ◽  
Annemarie Gillespie ◽  
Elaine J. Carlson ◽  
Charles J. Epstein ◽  
A. S. Verkman
Keyword(s):  
Mouse Model ◽  
Diabetes Insipidus ◽  
Neonatal Mortality ◽  
Nephrogenic Diabetes Insipidus ◽  
Aquaporin 2

scholarly journals Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus.

1997 ◽  
Vol 8 (12) ◽  
pp. 1855-1862 ◽  
Author(s):  
R Vargas-Poussou ◽  
L Forestier ◽  
M D Dautzenberg ◽  
P Niaudet ◽  
M Déchaux ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Nephrogenic Diabetes Insipidus ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Single Strand Conformational Polymorphism ◽  
Aquaporin 2 ◽  
Congenital Nephrogenic Diabetes Insipidus ◽  
V2 Receptor ◽  
Aqp2 Gene

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by renal tubular insensitivity to the antidiuretic effect of arginine vasopressin (AVP). In a large majority of the cases, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remaining cases, the disease is autosomal recessive or dominant and, for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. Fourteen probands belonging to 12 families were analyzed by single-strand conformational polymorphism and direct sequencing of the AVPR2 and AQP2 genes. Ten mutations of the AVPR2 gene (six previously reported mutations and four novel mutations: G107E, W193X, L43P, and 15delC) were identified. Three mutations of the AQP2 gene were also identified in two patients: the first patient is homozygous for the R85X mutation and the second is a compound heterozygote for V168 M and S216P mutations. Extrarenal responses to infusion of the strong V2 agonist 1-desamino-8-D-arginine vasopressin allowed AVPR2- and AQP2-associated forms of CNDI to be distinguished in three patients. This test also identified an unexpectedly high urinary osmolality (614 mosmol/kg) in a patient with a P322S mutation of AVPR2 gene and a mild form of CNDI.

scholarly journals Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus

2006 ◽  
Vol 291 (2) ◽  
pp. F257-F270 ◽  
Author(s):  
Joris H. Robben ◽  
Nine V. A. M. Knoers ◽  
Peter M. T. Deen
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Current Knowledge ◽  
Collecting Duct ◽  
Water Channel ◽  
Water Reabsorption ◽  
Aquaporin 2 ◽  
Electrolyte Disturbances ◽  
Genes Encoding ◽  
V2 Receptor

In the renal collecting duct, water reabsorption is regulated by the antidiuretic hormone vasopressin (AVP). Binding of this hormone to the vasopressin V2 receptor (V2R) leads to insertion of aquaporin-2 (AQP2) water channels in the apical membrane, thereby allowing water reabsorption from the pro-urine to the interstitium. The disorder nephrogenic diabetes insipidus (NDI) is characterized by the kidney's inability to concentrate pro-urine in response to AVP, which is mostly acquired due to electrolyte disturbances or lithium therapy. Alternatively, NDI is inherited in an X-linked or autosomal fashion due to mutations in the genes encoding V2R or AQP2, respectively. This review describes the current knowledge of the cell biological causes of NDI and how these defects may explain the patients' phenotypes. Also, the increased understanding of these cellular defects in NDI has opened exciting initiatives in the development of novel therapies for NDI, which are extensively discussed in this review.

scholarly journals New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels.

1997 ◽  
Vol 8 (2) ◽  
pp. 242-248 ◽  
Author(s):  
S M Mulders ◽  
N V Knoers ◽  
A F Van Lieburg ◽  
L A Monnens ◽  
E Leumann ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Water Permeability ◽  
Nephrogenic Diabetes Insipidus ◽  
Autosomal Recessive ◽  
Plasma Membranes ◽  
Collecting Duct ◽  
Water Channels ◽  
Wild Type ◽  
Aqp2 Gene ◽  
New Mutations

Nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine in response to vasopressin. The autosomal recessive form of NDI is caused by mutations in the AQP2 gene, encoding the vasopressin-regulated water channel of the kidney collecting duct. This report presents three new mutations in the AQP2 gene that cause NDI, resulting in A147T-, T126M-, or N68S-substituted AQP2 proteins. Expression of the A147T and T126M mutant AQP2 proteins in Xenopus oocytes revealed a relatively small, but significant increase in water permeability, whereas the water permeability of N68S expressing oocytes was not increased. cRNA encoding missense and wild-type AQP2 were equally stable in oocytes. Immunoblots of oocyte lysates showed that only the A147T mutant protein was less stable than wild-type AQP2. The mutant AQP2 proteins showed, in addition to the wild-type 29-kd band, an endoplasmic reticulum-retarded form of AQP2 of approximately 32 kd. Immunoblotting and immunocytochemistry demonstrated only intense labeling of the plasma membranes of oocytes expressing wild-type AQP2. In summary, two mutant AQP2 proteins encoded in NDI are functional water channels. Therefore, the major cause underlying autosomal recessive NDI is the misrouting of AQP2 mutant proteins.

scholarly journals Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2

2008 ◽  
Vol 294 (4) ◽  
pp. F702-F709 ◽  
Author(s):  
Gheun-Ho Kim ◽  
Nak Won Choi ◽  
Ju-Young Jung ◽  
Ji-Hyun Song ◽  
Chang Hwa Lee ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Urinary Concentration ◽  
Prostaglandin E ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Cox 2

Prostaglandin E2 may antagonize vasopressin-stimulated salt absorption in the thick ascending limb and water absorption in the collecting duct. Blockade of prostaglandin E2 synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) enhances urinary concentration, and these agents have antidiuretic effects in patients with nephrogenic diabetes insipidus (NDI) of different etiologies. Because renal prostaglandins are derived largely from cyclooxygenase-2 (COX-2), we hypothesized that treatment of NDI with a COX-2 inhibitor may relieve polyuria through increased expression of Na-K-2Cl cotransporter type 2 (NKCC2) in the thick ascending limb and aquaporin-2 (AQP2) in the collecting duct. To test this hypothesis, semiquantitative immunoblotting and immunohistochemistry were carried out from the kidneys of lithium-induced NDI rats with and without COX-2 inhibition. After male Sprague-Dawley rats were fed an LiCl-containing rat diet for 3 wk, the rats were randomly divided into control and experimental groups. The COX-2 inhibitor DFU (40 mg·kg−1·day−1) was orally administered to the experimental rats for an additional week. Treatment with the COX-2 inhibitor significantly relieved polyuria and raised urine osmolality. Semiquantitative immunoblotting using whole-kidney homogenates revealed that COX-2 inhibition caused significant increases in the abundance of AQP2 and NKCC2. Immunohistochemistry for AQP2 and NKCC2 confirmed the effects of COX-2 inhibition in lithium-induced NDI rats. The upregulation of AQP2 and NKCC2 in response to the COX-2 inhibitor may underlie the therapeutic mechanisms by which NSAIDs enhance antidiuresis in patients with NDI.

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