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Peter M T Deen - One of the best experts on this subject based on the ideXlab platform.
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acetazolamide attenuates lithium induced Nephrogenic Diabetes Insipidus
Journal of The American Society of Nephrology, 2016Co-Authors: Theun De Groot, Johannes Loffing, Marleen L A Kortenoeven, Anne P Sinke, Ruben Baumgarten, Jack F M Wetzels, Mohammad Alsady, Olivier Devuyst, Peter M T DeenAbstract:To reduce lithium-induced Nephrogenic Diabetes Insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
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x ray structure of human aquaporin 2 and its implications for Nephrogenic Diabetes Insipidus and trafficking
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Anna Frick, Peter M T Deen, U K Eriksson, F P De Mattia, Fredrik Oberg, Kristina Hedfalk, Richard Neutze, W J De Grip, Susanna TornrothhorsefieldAbstract:Human aquaporin 2 (AQP2) is a water channel found in the kidney collecting duct, where it plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin and defective trafficking results in Nephrogenic Diabetes Insipidus (NDI). Here we present the X-ray structure of human AQP2 at 2.75 A resolution. The C terminus of AQP2 displays multiple conformations with the C-terminal α-helix of one protomer interacting with the cytoplasmic surface of a symmetry-related AQP2 molecule, suggesting potential protein-protein interactions involved in cellular sorting of AQP2. Two Cd(2+)-ion binding sites are observed within the AQP2 tetramer, inducing a rearrangement of loop D, which facilitates this interaction. The locations of several NDI-causing mutations can be observed in the AQP2 structure, primarily situated within transmembrane domains and the majority of which cause misfolding and ER retention. These observations provide a framework for understanding why mutations in AQP2 cause NDI as well as structural insights into AQP2 interactions that may govern its trafficking.
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hydrochlorothiazide attenuates lithium induced Nephrogenic Diabetes Insipidus independently of the sodium chloride cotransporter
American Journal of Physiology-renal Physiology, 2014Co-Authors: Anne P Sinke, Marleen L A Kortenoeven, Theun De Groot, Ruben Baumgarten, Jack F M Wetzels, Olivier Devuyst, Peter M T DeenAbstract:Lithium is the most common cause of Nephrogenic Diabetes Insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.
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congenital Nephrogenic Diabetes Insipidus the current state of affairs
Pediatric Nephrology, 2012Co-Authors: Daniel J Wesche, Peter M T Deen, Nine V A M KnoersAbstract:The anti-diuretic hormone arginine vasopressin (AVP) is released from the pituitary upon hypovolemia or hypernatremia, and regulates water reabsorption in the renal collecting duct principal cells. Binding of AVP to the arginine vasopressin receptor type 2 (AVPR2) in the basolateral membrane leads to translocation of aquaporin 2 (AQP2) water channels to the apical membrane of the collecting duct principal cells, inducing water permeability of the membrane. This results in water reabsorption from the pro-urine into the medullary interstitium following an osmotic gradient. Congenital Nephrogenic Diabetes Insipidus (NDI) is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their pro-urine, which leads to a high risk of dehydration. This review focuses on the current knowledge regarding the cell biological aspects of congenital X-linked, autosomal-recessive and autosomal-dominant NDI while specifically addressing the latest developments in the field. Based on deepened mechanistic understanding, new therapeutic strategies are currently being explored, which we also discuss here.
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intracellular activation of vasopressin v2 receptor mutants in Nephrogenic Diabetes Insipidus by nonpeptide agonists
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Joris H Robben, Marleen L A Kortenoeven, Nine V A M Knoers, Mozes Sze, Chris Yae, Graeme Milligan, Viola Oorschot, Judith Klumperman, Peter M T DeenAbstract:Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocation of aquaporin-2 to the apical membrane. Moreover, in contrast to plasma membrane V2R, degradation of intracellular V2R mutants is not increased by their activation. Our data reveal that G protein-coupled receptors (GPCRs) normally active at the plasma membrane can be activated intracellularly and that intracellular activation does not induce their degradation; the data also indicate that nonpeptide agonists constitute highly promising therapeutics for diseases caused by misfolded GPCRs in general, and NDI in particular.
Marleen L A Kortenoeven - One of the best experts on this subject based on the ideXlab platform.
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acetazolamide attenuates lithium induced Nephrogenic Diabetes Insipidus
Journal of The American Society of Nephrology, 2016Co-Authors: Theun De Groot, Johannes Loffing, Marleen L A Kortenoeven, Anne P Sinke, Ruben Baumgarten, Jack F M Wetzels, Mohammad Alsady, Olivier Devuyst, Peter M T DeenAbstract:To reduce lithium-induced Nephrogenic Diabetes Insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
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hydrochlorothiazide attenuates lithium induced Nephrogenic Diabetes Insipidus independently of the sodium chloride cotransporter
American Journal of Physiology-renal Physiology, 2014Co-Authors: Anne P Sinke, Marleen L A Kortenoeven, Theun De Groot, Ruben Baumgarten, Jack F M Wetzels, Olivier Devuyst, Peter M T DeenAbstract:Lithium is the most common cause of Nephrogenic Diabetes Insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.
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intracellular activation of vasopressin v2 receptor mutants in Nephrogenic Diabetes Insipidus by nonpeptide agonists
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Joris H Robben, Marleen L A Kortenoeven, Nine V A M Knoers, Mozes Sze, Chris Yae, Graeme Milligan, Viola Oorschot, Judith Klumperman, Peter M T DeenAbstract:Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocation of aquaporin-2 to the apical membrane. Moreover, in contrast to plasma membrane V2R, degradation of intracellular V2R mutants is not increased by their activation. Our data reveal that G protein-coupled receptors (GPCRs) normally active at the plasma membrane can be activated intracellularly and that intracellular activation does not induce their degradation; the data also indicate that nonpeptide agonists constitute highly promising therapeutics for diseases caused by misfolded GPCRs in general, and NDI in particular.
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amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant Nephrogenic Diabetes Insipidus
Kidney International, 2009Co-Authors: Marleen L A Kortenoeven, Jack F M Wetzels, Stephen Shaw, Hanspeter Gaeggeler, Bernard C Rossier, Peter M T DeenAbstract:Lithium therapy frequently induces Nephrogenic Diabetes Insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site for lithium and the beneficial effect of amiloride may be through inhibiting lithium entry. Using a mouse collecting duct cell line, we found that vasopressin caused an increase in Aquaporin 2 (AQP2) expression which was reduced by clinically relevant lithium concentrations similar to what is seen with in vivo models of this disease. Further amiloride or benzamil administration prevented this lithium-induced downregulation of AQP2. Amiloride reduced transcellular lithium transport, intracellular lithium concentration, and lithium-induced inactivation of glycogen synthase kinase 3β. Treatment of rats with lithium downregulated AQP2 expression, reduced the principal-to-intercalated cell ratio, and caused polyuria, while simultaneous administration of amiloride attenuated all these changes. These results show that ENaC is the major entry site for lithium in principal cells both in vitro and in vivo . Blocking lithium entry with amiloride attenuates lithium-induced Diabetes Insipidus, thus providing a rationale for its use in treating this disorder.
Daniel G. Bichet - One of the best experts on this subject based on the ideXlab platform.
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Nephrogenic Diabetes Insipidus
Current Opinion in Pediatrics, 2017Co-Authors: Detlef Bockenhauer, Daniel G. BichetAbstract:PURPOSE OF REVIEW: In Nephrogenic Diabetes Insipidus (NDI), the kidney is unable to concentrate urine despite elevated concentrations of the antidiuretic hormone arginine-vasopressin. In congenital NDI, polyuria and polydipsia are present from birth and should be immediately recognized to avoid severe episodes of dehydration. Unfortunately, NDI is still often recognized late after a 'diagnostic odyssey' involving false leads and dangerous treatments.Once diagnosed, appropriate treatment can be started. Moreover, laboratory studies have identified promising new compounds, which may help achieve urinary concentration independent of vasopressin. RECENT FINDINGS: MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome.We distinguish two types of hereditary NDI: a 'pure' type with loss of water only and a complex type with loss of water and ions. Mutations in the AVPR2 or AQP2 genes, encoding the vasopressin V2 receptor and the water channel Aquaporin2, respectively, lead to a 'pure' NDI with loss of water but normal conservation of ions. Mutations in genes that encode membrane proteins involved in sodium chloride reabsorption in the thick ascending limb of Henle's loop lead to Bartter syndrome, a complex polyuric-polydipsic disorder often presenting with polyhydramnios. A new variant of this was recently identified: seven families were described with transient antenatal Bartter's syndrome, polyhydramnios and MAGED2 mutations.Multiple compounds have been identified experimentally that may stimulate urinary concentration independently of the vasopressin V2 receptor. These compounds may provide new treatments for patients with X-linked NDI. SUMMARY: A plea for early consideration of the diagnosis of NDI, confirmation by phenotypic and/or genetic testing and appropriate adjustment of treatment in affected patients.
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X-linked Nephrogenic Diabetes Insipidus mutations in North America and the Hopewell hypothesis
2016Co-Authors: Daniel G. Bichet, Marie-franoise Arthus, Michble Lonergan, Geoffrey N. Hendy, Ann Jose Paradis, Mary T. Fujiwara, Kenneth L Morgan, I** Martin C. GregoryAbstract:In X-linked Nephrogenic Diabetes Insipidus (NDI) the urine of male patients is not concentrated after the administration ofthe antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V 2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 af-fected male patients from the "Hopewell " kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell " mutation, W71X, is a single base substitution (G A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and ofthe four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene. (J. Clin. Invest. 1993. 92:1262-1268.) Key words: deoxyribonu-cleic acid mutational analysis * vasopressins * heterozygote de-tection * G-proteins * vasopressin receptor
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DISEASE OF THE MONTH Congenital Nephrogenic Diabetes Insipidus
2016Co-Authors: See Profile, Daniel G. Bichet, Alexander Oksche, Justus-liebig-universität Gießen, Walter RosenthaltAbstract:Congenital Nephrogenic Diabetes Insipidus (NDI) is a rare disorder of the kidney characterized by the failure to concen-trate urine despite normal or elevated plasma concentrations of the antidiuretic hormone arginine vasopressin (AVP). The identifica-tion, characterization, and mutational analysis of two different genes, i.e., the AVP receptor 2 gene (AVPR2) and the vasopressin-sensitive water channel gene (aquaporin-2 [AQP2]), provide the basis for our understanding of two different hereditary forms of ND!: X-linked ND! and autosomal recessive NDI. A majority (>90%) of congenital ND! patients have AVPR2 mutations: Of 1 15 families with congenital ND! that were referred to our labo-ratories in Montreal and Berlin, 105 families had A VPR2 muta-tions and 10 had AQP2 mutations. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of th
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genetic forms of Nephrogenic Diabetes Insipidus ndi vasopressin receptor defect x linked and aquaporin defect autosomal recessive and dominant
Best Practice & Research Clinical Endocrinology & Metabolism, 2016Co-Authors: Daniel G. Bichet, Detlef BockenhauerAbstract:Nephrogenic Diabetes Insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration.
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pathophysiology diagnosis and management of Nephrogenic Diabetes Insipidus
Nature Reviews Nephrology, 2015Co-Authors: Detlef Bockenhauer, Daniel G. BichetAbstract:Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In Nephrogenic Diabetes Insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments.
Theun De Groot - One of the best experts on this subject based on the ideXlab platform.
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acetazolamide attenuates lithium induced Nephrogenic Diabetes Insipidus
Journal of The American Society of Nephrology, 2016Co-Authors: Theun De Groot, Johannes Loffing, Marleen L A Kortenoeven, Anne P Sinke, Ruben Baumgarten, Jack F M Wetzels, Mohammad Alsady, Olivier Devuyst, Peter M T DeenAbstract:To reduce lithium-induced Nephrogenic Diabetes Insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
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Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus.
'American Society of Nephrology (ASN)', 2016Co-Authors: Theun De Groot, Sinke A.p., Kortenoeven M.l.a., Baumgarten R., Devuyst O., Wetzels J.f.m., Loffing J., Alsady M., Deen P.m.t.Abstract:Contains fulltext : 172732.pdf (publisher's version ) (Closed access)To reduce lithium-induced Nephrogenic Diabetes Insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.1 juli 201
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hydrochlorothiazide attenuates lithium induced Nephrogenic Diabetes Insipidus independently of the sodium chloride cotransporter
American Journal of Physiology-renal Physiology, 2014Co-Authors: Anne P Sinke, Marleen L A Kortenoeven, Theun De Groot, Ruben Baumgarten, Jack F M Wetzels, Olivier Devuyst, Peter M T DeenAbstract:Lithium is the most common cause of Nephrogenic Diabetes Insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.
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Hydrochlorothiazide attenuates lithium-induced Nephrogenic Diabetes Insipidus independently of the sodium-chloride cotransporter
'American Physiological Society', 2014Co-Authors: Sinke A.p., Theun De Groot, Kortenoeven M.l.a., Baumgarten R., Devuyst O., Wetzels J.f.m., Loffing J., Deen P.m.t.Abstract:Contains fulltext : 138192.pdf (publisher's version ) (Closed access)Lithium is the most common cause of Nephrogenic Diabetes Insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition
Jack F M Wetzels - One of the best experts on this subject based on the ideXlab platform.
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acetazolamide attenuates lithium induced Nephrogenic Diabetes Insipidus
Journal of The American Society of Nephrology, 2016Co-Authors: Theun De Groot, Johannes Loffing, Marleen L A Kortenoeven, Anne P Sinke, Ruben Baumgarten, Jack F M Wetzels, Mohammad Alsady, Olivier Devuyst, Peter M T DeenAbstract:To reduce lithium-induced Nephrogenic Diabetes Insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
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hydrochlorothiazide attenuates lithium induced Nephrogenic Diabetes Insipidus independently of the sodium chloride cotransporter
American Journal of Physiology-renal Physiology, 2014Co-Authors: Anne P Sinke, Marleen L A Kortenoeven, Theun De Groot, Ruben Baumgarten, Jack F M Wetzels, Olivier Devuyst, Peter M T DeenAbstract:Lithium is the most common cause of Nephrogenic Diabetes Insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.
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amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant Nephrogenic Diabetes Insipidus
Kidney International, 2009Co-Authors: Marleen L A Kortenoeven, Jack F M Wetzels, Stephen Shaw, Hanspeter Gaeggeler, Bernard C Rossier, Peter M T DeenAbstract:Lithium therapy frequently induces Nephrogenic Diabetes Insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site for lithium and the beneficial effect of amiloride may be through inhibiting lithium entry. Using a mouse collecting duct cell line, we found that vasopressin caused an increase in Aquaporin 2 (AQP2) expression which was reduced by clinically relevant lithium concentrations similar to what is seen with in vivo models of this disease. Further amiloride or benzamil administration prevented this lithium-induced downregulation of AQP2. Amiloride reduced transcellular lithium transport, intracellular lithium concentration, and lithium-induced inactivation of glycogen synthase kinase 3β. Treatment of rats with lithium downregulated AQP2 expression, reduced the principal-to-intercalated cell ratio, and caused polyuria, while simultaneous administration of amiloride attenuated all these changes. These results show that ENaC is the major entry site for lithium in principal cells both in vitro and in vivo . Blocking lithium entry with amiloride attenuates lithium-induced Diabetes Insipidus, thus providing a rationale for its use in treating this disorder.