Nephrogenic Diabetes Insipidus

1996 ◽  
Vol 17 (4) ◽  
pp. 145-146
Author(s):  
Corrine Benchimol
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Duct Cell ◽  
Cell Binding ◽  
Luminal Membrane ◽  
Concentrate Urine ◽  
V2 Receptor ◽  
Final Effect

Nephrogenic diabetes insipidus (NDI) is a disorder, either congenital or acquired, in which antidiuretic hormone (ADH) secretion is normal, but the ability to concentrate urine is reduced because of insensitivity of the collecting tubule to ADH. The antidiuretic action of arginine vasopressin requires binding of the hormone to the renal type V2 receptor on the basolateral membrane of the collecting duct principal cell. Binding results in activation of adenylate cyclase, generation of cAMP, and increased reabsorption of water across the apical membrane of the renal collecting duct cell. The defect in NDI may be located at any of the steps from binding of vasopressin to the final effect of the hormone on the luminal membrane.

scholarly journals Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus

2007 ◽  
Vol 292 (1) ◽  
pp. F253-F260 ◽  
Author(s):  
J. H. Robben ◽  
M. Sze ◽  
N. V. A. M. Knoers ◽  
P. M. T. Deen
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Basolateral Membrane ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
High Affinity ◽  
Vasopressin V2 Receptor ◽  
Camp Generation ◽  
V2 Receptor

Intracellular retention of a functional vasopressin V2 receptor (V2R) is a major cause of congenital nephrogenic diabetes insipidus (NDI) and rescue of V2R mutants by nonpeptide antagonists may restore their basolateral membrane (BM) localization and function. However, the criteria for efficient functional rescue of G protein-coupled receptor (GPCR) mutants at clinically feasible antagonist concentrations are unknown. We found that the four nonpeptide antagonists SR49059, OPC31260 , OPC41061 , and SR121463B induced maturation and rescued the BM expression of eight of nine different V2R mutants, stably expressed in physiologically relevant polarized cells. The extent of maturation and rescued BM expression correlated with the antagonists' concentration and affinity for the V2R. Displacement of the antagonists by AVP and subsequent cAMP generation inversely correlated with the antagonists' affinities for the V2R but is partially influenced by antagonist-specific aspects. Despite limited increases in maturation and cell-surface expression of V2R mutants, the low-affinity SR49059 optimally induced functional rescue at high concentrations, due to its easy displacement by vasopressin. At clinically feasible antagonist concentrations, however, only the high-affinity antagonists OPC31260 and OPC41061 induced functional rescue, as at these concentrations the extent of BM expression became limited. In conclusion, functional rescue of mutant V2Rs at clinically feasible concentrations is most effective with high-affinity antagonists. As OPC31260 and OPC41061 are clinically safe, they are promising candidates to relieve NDI. Moreover, as numerous other diseases are caused by endoplasmic reticulum-retained GPCRs for which cell-permeable antagonists become available, our finding that high-affinity antagonists are superior is anticipated to be important for pharmacotherapy development of these diseases.

scholarly journals Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Federica Prosperi ◽  
Yoko Suzumoto ◽  
Pierluigi Marzuillo ◽  
Vincenzo Costanzo ◽  
Sabina Jelen ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Basolateral Membrane ◽  
Functional Characterization ◽  
Urinary Concentration ◽  
Loss Of Function ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor

Abstract Nephrogenic diabetes insipidus (NDI) is a rare tubulopathy characterized by urinary concentration defect due to renal resistance to vasopressin. Loss-of-function mutations of vasopressin V2 receptor (V2R) gene (AVPR2) is the most common cause of the disease. We have identified five novel mutations L86P, R113Q, C192S, M272R, and W323_I324insR from NDI-affected patients. Functional characterization of these mutants revealed that R113Q and C192S were normally localized at the basolateral membrane of polarized Madin-Darby Canine Kidney (MDCK) cells and presented proper glycosylation maturation. On the other side, L86P, M272R, and W323_I324insR mutants were retained in endoplasmic reticulum and exhibited immature glycosylation and considerably reduced stability. All five mutants were resistant to administration of vasopressin analogues as evaluated by defective response in cAMP release. In order to rescue the function of the mutated V2R, we tested VX-809, sildenafil citrate, ibuprofen and tolvaptan in MDCK cells. Among these, tolvaptan was effective in rescuing the function of M272R mutation, by both allowing proper glycosylation maturation, membrane sorting and response to dDAVP. These results show an important proof of concept for the use of tolvaptan in patients affected by M272R mutation of V2R causing NDI.

scholarly journals Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model

2005 ◽  
Vol 289 (2) ◽  
pp. F265-F272 ◽  
Author(s):  
J. H. Robben ◽  
N. V. A. M. Knoers ◽  
P. M. T. Deen
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Transmembrane Domain ◽  
Cell Model ◽  
Basolateral Membrane ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Intracellular Camp ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor

X-linked nephrogenic diabetes insipidus (NDI) is caused by mutations in the gene encoding the vasopressin V2 receptor (V2R). For the development of a tailored therapy for NDI, knowledge of the cellular fate of V2R mutants is needed. It would be useful when this fate could be predicted from the location and type of mutation. To identify similarities and differences in localization, maturation, stability, and degradation of COOH-terminal GFP-tagged V2R mutants, we stably expressed nine mutants in polarized Madin-Darby canine kidney cells. The mutants V2R-L44P, -Δ62–64, -I130F, -S167T, -S167L, and -V206D were mainly expressed in the endoplasmic reticulum (ER) as immature proteins. These mutants had relatively short half-lives due to proteasomal degradation, except for V2R-Δ62–64. In contrast, V2R-R113W, -G201D, and -T204N were expressed in the ER and in the basolateral membrane as immature, high-mannose glycosylated, and mature complex-glycosylated proteins. The immature forms of V2R-R113W and -T204N, but not V2R-G201D, were rapidly degraded. The mature forms varied extensively in their stability and were degraded by only lysosomes (V2R-T204N and wild-type V2R) or lysosomes and proteasomes (V2R-G201D, -R113W). These data reveal that most missense V2R mutations lead to retention in the ER and suggest that mutations that likely distort a transmembrane domain or introduce a charged amino acid close to it make a V2R mutant more prone to ER retention. Because six of the mutants tested showed significant increases in intracellular cAMP levels on transient expression in COS cells, activation of these six receptors following rescue of cell-surface expression might provide a cure for NDI patients.

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.

Vectorial efflux of cGMP and its dependence on sodium in the cortical collecting duct

1996 ◽  
Vol 271 (6) ◽  
pp. R1676-R1681 ◽  
Author(s):  
B. A. Stoos ◽  
J. L. Garvin
Keyword(s):  
Cultured Cells ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Transport Mechanisms ◽  
Cortical Collecting Duct ◽  
Phosphodiesterase Inhibition ◽  
Luminal Membrane ◽  
Sodium Dependent ◽  
Independent Mechanism ◽  
Presence And Absence

Guanosine 3',5'-cyclic monophosphate (cGMP) is an important second messenger that regulates transport in the nephron. We propose that the transport mechanisms that remove cGMP from the cell are different in the luminal and basolateral membranes of the cortical collecting duct (CCD). We examined efflux of cGMP from cultured and isolated perfused CCDs in response to atrial natriuretic factor (ANF) and nitric oxide (NO). In the presence of phosphodiesterase inhibition, these compounds resulted in preferential efflux of cGMP across the basolateral membrane in both cultured and isolated CCDs. In the presence of ANF, efflux was five times higher across the basolateral than the luminal membrane in cultured CCD cells (n = 14). In isolated CCDs, effluxes across the basolateral and luminal membranes were 1.02 +/- 0.2 and 0.03 +/- 0.01 fmol.mm-1.min-1, respectively, in the presence of ANF (n = 6; P < 0.007) and 0.87 +/- 0.21 and 0.02 +/- 0.01 fmol.mm-1.min-1, respectively, in the presence of NO (n = 6; P < 0.011). Efflux across the basolateral membrane in the presence and absence of sodium was 37 +/- 7.3 and 19.9 +/- 5 fmol.cm-2.min-1, respectively, in cultured cells (n = 12; P < 0.044) and 1.02 +/- 0.2 (n = 6) and 0.41 +/- 0.12 (n = 5) fmol.mm-1.min-1 in isolated perfused tubules (P < 0.042). There was no difference in luminal transport in the presence and absence of sodium in either model. We conclude that there are at least two different mechanisms involved in the removal of cGMP from the cell, one sodium dependent and the other sodium independent. The basolateral membrane appears to contain both, whereas the luminal membrane contains only the sodium-independent mechanism.

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 A Novel Mutation in the AVPR2 Gene in a Palestinian Family with Nephrogenic Diabetes Insipidus

2017 ◽  
Vol 07 (01) ◽  
pp. e1-e3
Author(s):  
Abdulsalam Abu-Libdeh ◽  
Isaiah Wexler ◽  
Imad Dweikat ◽  
David Zangen ◽  
Bassam Abu-Libdeh
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Novel Mutation ◽  
Collecting Duct ◽  
Failure To Thrive ◽  
Male Infant ◽  
Gene Encoding ◽  
Exon 2 ◽  
Recessive Form ◽  
V2 Vasopressin Receptor

AbstractNephrogenic diabetes insipidus (NDI) is a urinary concentrating defect resulting from resistance of the collecting duct to the antidiuretic action of vasopressin (AVP). The X-linked recessive form is the most frequent genetic cause of inherited NDI and can be caused by mutations in the gene encoding the V2 vasopressin receptor (AVPR2). A Palestinian male infant presented in the neonatal period with failure to thrive, vomiting, irritability, fever, and polyuria, and had biochemical findings consistent with NDI. The diagnosis of NDI was established based on the clinical picture, absent response to desmopressin, and a similarly affected elder brother. Sequencing of the AVPR2 gene for the patient and his affected brother revealed a novel missense mutation with replacement of G by A in codon 82 located in exon 2 (TGC → TAC), causing a cysteine to tyrosine substitution (C82Y). Testing of the mother showed that she was the carrier of that mutation. This is the identified AVPR2 mutation in a Palestinian family. Knowledge of these mutations will allow genetic counseling and early diagnosis of affected males.

The isolated C-terminus of polycystin-1 promotes increased ATP-stimulated chloride secretion in a collecting duct cell line

2003 ◽  
Vol 104 (3) ◽  
pp. 217-221 ◽  
Author(s):  
Kimberly M. HOOPER ◽  
Robert J. UNWIN ◽  
Michael SUTTERS
Keyword(s):  
Fusion Protein ◽  
Cell Line ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Duct Cell ◽  
Chloride Secretion ◽  
Cortical Collecting Duct ◽  
Membrane Expression ◽  
Fusion Protein Expression ◽  
C Terminus

Cyst expansion in autosomal dominant polycystic kidney disease (ADPKD) requires accumulation of fluid into the cyst lumen, which is probably driven by aberrant chloride secretion by the cyst lining epithelium. Extracellular ATP is a potent stimulus for chloride secretion in many epithelial systems, and provides a plausible mechanism for secretion in ADPKD. Therefore the link between polycystin-1 and ATP-stimulated chloride secretion was investigated in the M1 cortical collecting duct cell line. M1 cells were stably transfected with a glucocorticoid-inducible cytoplasmic C-terminal polycystin-1 construct fused to a membrane expression cassette. Induction of fusion protein expression was associated with augmentation of ATP-stimulated transepithelial chloride secretion. After nystatin-induced permeabilization of the basolateral membrane, it was determined that expression of the polycystin fusion protein modulated an ATP-responsive apical chloride conductance. It is concluded that up-regulation of ATP-stimulated chloride secretion might play a significant role in cyst expansion in ADPKD.

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