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Action of arginine vasopressin (AVP) in the collecting duct principal cells. Upon the binding of AVP to its cognate receptor AVPR2 at the basolateral membrane, a stimulatory G protein α subunit (G s ) activates adenylyl cyclase and increases cyclic adenosine monophosphate (cAMP) intracellular concentrations. This, in turn, activates protein kinase A (PKA), which phosphorylates many substrates, including AQP2 and RhoA (full lines). The partial depolymerization of the sub-apical actin cytoskeleton facilitates the apical exocytosis of AQP2-storage vesicles (dotted lines). Water enters the cells via de novo inserted AQP2 tetramers at the apical membrane and leaves the epithelial cells through AQP3 and AQP4 constitutively expressed at the basolateral membrane. AVP removal from the bloodstream allows AQP2 endocytosis and recycling through early endosomes (dotted lines).
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Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key ev...
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Context 1
... particular, shrinkage of hypothalamic osmoreceptors or decreased activity of aortic and carotid baroreceptors [3] triggers the release of the antidiuretic hormone arginine vasopressin (AVP) from the posterior pituitary into the bloodstream [4,5]. The antidiuretic action of AVP (Figure 1) begins upon binding to type-2 vasopressin receptor (AVPR2) [6], a G protein-coupled receptor localized at the basolateral plasma membrane of the principal cells of the kidney collecting duct (Figure 1). Once activated by AVP, AVPR2 initiates a signal transduction cascade that consists of the activation of adenylate cyclase (AC) via the stimulatory G (Gs) protein, an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration, and the activation of protein kinase A (PKA). ...
Context 2
... particular, shrinkage of hypothalamic osmoreceptors or decreased activity of aortic and carotid baroreceptors [3] triggers the release of the antidiuretic hormone arginine vasopressin (AVP) from the posterior pituitary into the bloodstream [4,5]. The antidiuretic action of AVP (Figure 1) begins upon binding to type-2 vasopressin receptor (AVPR2) [6], a G protein-coupled receptor localized at the basolateral plasma membrane of the principal cells of the kidney collecting duct (Figure 1). Once activated by AVP, AVPR2 initiates a signal transduction cascade that consists of the activation of adenylate cyclase (AC) via the stimulatory G (Gs) protein, an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration, and the activation of protein kinase A (PKA). ...
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Citations
... In the human body, it is critical to maintain plasma tonicity within its normal range [12], since extracellular osmolality has a crucial role in regulating cell shape and intracellular concentrations of ions and other osmolytes, as well as cell function [13]. ...
... This, in turn, activates adenylyl cyclase to convert ATP to cyclic AMP. Cyclic AMP, as a second messenger, induces activation of protein kinase A, which phosphorylates AQP2 tetramers [12]. Phosphorylated AQP2 tetramers are transported to the apical membrane of principal cells to form water channels for water reabsorption and this subsequently concentrates the urine [12]. ...
... Cyclic AMP, as a second messenger, induces activation of protein kinase A, which phosphorylates AQP2 tetramers [12]. Phosphorylated AQP2 tetramers are transported to the apical membrane of principal cells to form water channels for water reabsorption and this subsequently concentrates the urine [12]. ...
Background: Nephrogenic diabetes insipidus (NDI) is a rare renal disorder that can be congenital, and is caused by mutations in either aquaporin 2 or arginine vasopressin receptor 2, or it can be secondary to kidney disease or electrolyte imbalance. The clinical signs of NDI include polyuria, compensatory polydipsia, hypernatremic dehydration, and growth retardation without prompt treatment. In this report, we present the case of a patient with congenital NDI who was later diagnosed with acute lymphoblastic leukemia (ALL). With dexamethasone treatment, he had uncontrolled polyuria and polydipsia. Our aim was to concentrate on the impact of steroids on the kidneys.
Case Report: Our patient presented at the age of 9 months with signs of severe dehydration that were associated with polyuria. His laboratory examinations revealed hypernatremia and decreased urine osmolality. He was diagnosed with NDI and his exome sequence revealed a homozygous mutation at the nucleotide position AQP2 NM_000486.6: c.374C>T (p.Thr125Met). He was treated with hydrochlorothiazide and amiloride. Then, at age 19 months, he presented with gastroenteritis and a complete blood count (CBC) showed high white blood cell count and blast cells. He was diagnosed with (ALL) and began receiving chemotherapy, during which again developed polydipsia and polyuria, which could not be controlled with an increased dosage of hydrochlorothiazide.
Conclusions: We report a rare case of NDI caused by a missense mutation in the aquaporin 2 gene. One year later, the child developed ALL, and treatment with dexamethasone led to an uncompensated state of polydipsia and polyuria.
... Mutations affecting the AVPR2 gene represent 90% of cases and have an X-linked pattern of inheritance. 2,3 In this report, we describe the case of a 13-year-old male known with CNDI who experienced a pedestrian vehicle accident leading to coma due to a head injury. Intra-operatively, severe hypernatraemia and polyuria were observed. ...
Congenital nephrogenic diabetes insipidus (CNDI) is a rare disorder. The condition is characterised by an inability of distal nephron segments to respond to normal or raised concentrations of serum antidiuretic hormone. In this report, we describe the case of a 13-year-old male known with CNDI who experienced a pedestrian vehicle accident leading to coma following a head injury. Intra-operatively, severe hypernatraemia and polyuria were observed. Following an inadequate response to conventional therapy, acetazolamide was prescribed resulting in an immediate response to therapy. To the best of our knowledge, acetazolamide has not been previously documented as a therapeutic option for CNDI. Additional research is necessary before considering the recommendation of acetazolamide for cases of NDI that do not respond adequately to conventional treatments.
... Congenital nephrogenic diabetes insipidus (CNDI), a rare hereditary, mainly X-linked renal disorder [1,2], is characterized by the inability of the kidneys to concentrate urine in response to the antidiuretic hormone arginine vasopressin (AVP); as a result, large volumes of unconcentrated urine are excreted. Clinical manifestations of CNDI include polyuria, compensatory polydipsia, dehydration, electrolyte disturbances (hypernatremia and hyperchloremia), and, without prompt treatment, developmental delay [2,3]. ...
Congenital nephrogenic diabetes insipidus (CNDI), a rare hereditary disorder, is characterized by the inability of the kidneys to concentrate urine in response to the antidiuretic hormone arginine vasopressin (AVP); as a result, large volumes of unconcentrated urine are excreted. In addition to the clinical manifestations of CNDI, such as dehydration and electrolyte disturbances (hypernatremia and hyperchloremia), developmental delay can result without prompt treatment. In approximately 90% of cases, CNDI is an X-linked disease caused by mutations in the arginine vasopressin receptor 2 ( AVPR2 ) gene. In approximately 9% of cases, CNDI is an autosomal recessive disease caused by mutations in the water channel protein aquaporin 2 ( AQP2 ), and 1% of cases are autosomal dominant. We report a case of CNDI caused by a novel AVPR2 nonsense mutation, c.520C>T (p.Q174X), and cases of siblings in another family who had a different AVPR2 nonsense mutation, c.852G>A (p.W284X). Both cases responded well to treatment with hydrochlorothiazide and spironolactone. If CNDI is suspected, especially in carriers and neonates, aggressive genetic testing and early treatment may alleviate growth disorders and prevent irreversible central nervous system disorders and developmental delay.
... Congenital NDI is typically the result of mutations in the genes for AVPR2 or AQP2. AQP2-mutations constitute approximately 10% of these and at least 70 AQP2-mutations have been identified in NDI-patients 18,19 . A Figure 2. Structure of human AQP2 (a)Topographical representation of AQP2, with glycosylation site indicated in green, phosphorylation sites in yellow, and mutations of interest in red, blue and green. ...
Aquaporins are water channels found in the cell membrane, where they allow the passage of water molecules in and out of the cells. In the kidney collecting duct, arginine vasopressin-dependent trafficking of aquaporin-2 (AQP2) fine-tunes reabsorption of water from pre-urine, allowing precise regulation of the final urine volume. Point mutations in the gene for AQP2 may disturb this process and lead to nephrogenic diabetes insipidus (NDI), whereby patients void large volumes of highly hypo-osmotic urine. In recessive NDI, mutants of AQP2 are retained in the endoplasmic reticulum due to misfolding. Here we describe the structural and functional characterization of three AQP2 mutations associated with recessive NDI: T125M and T126M, situated close to a glycosylation site and A147T in the transmembrane region. Using a proteoliposome assay, we show that all three mutants permit the transport of water. The crystal structures of T125M and T126M together with biophysical characterization of all three mutants support that they retain the native structure, but that there is a significant destabilization of A147T. Our work provides unique molecular insights into the mechanisms behind recessive NDI as well as deepens our understanding of how misfolded proteins are recognized by the ER quality control system.
... Рекомендации по ведению таких пациентов направлены на восполнение потери жидкости с мочой адекватным количеством выпитой, в сочетании с низкосолевой диетой. Кроме того, возможно применение нестероидных противовоспалительных препаратов (НПВС) и диуретиков [13,14]. НПВС, такие как ибупрофен и индометацин, улучшают способность концентрировать мочу и уменьшают ее объем на 25-50%, а комбинация с гидрохлоротиазидом оказывает аддитивный эффект [13,14]. ...
... Кроме того, возможно применение нестероидных противовоспалительных препаратов (НПВС) и диуретиков [13,14]. НПВС, такие как ибупрофен и индометацин, улучшают способность концентрировать мочу и уменьшают ее объем на 25-50%, а комбинация с гидрохлоротиазидом оказывает аддитивный эффект [13,14]. Тиазидные диуретики эффективно снижают диурез при соблюдении диеты с очень низким содержанием натрия [13]. ...
... НПВС, такие как ибупрофен и индометацин, улучшают способность концентрировать мочу и уменьшают ее объем на 25-50%, а комбинация с гидрохлоротиазидом оказывает аддитивный эффект [13,14]. Тиазидные диуретики эффективно снижают диурез при соблюдении диеты с очень низким содержанием натрия [13]. Калийсберегающие диуретики, такие как амилорид, могут иметь аддитивный эффект с тиазидными диуретиками через механизм ингибирования потери калия, вызванной тиазидами [14]. ...
Congenital nephrogenic diabetes insipidus (CNDI, arginine vasopressin resistance) is a rare inherited disorder characterized by insensitivity of the kidney to the antidiuretic effect of vasopressin. NDI is clinically characterized by polyuria with hyposthenuria and nocturia and polydipsia. In the majority of cases, about 90%, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remaining cases, about 10%, the disease is autosomal recessive or dominant and, for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. To date, the nucleotide variants registered in AQP2 were sporadic, there is no data on the presence of «frequent» mutations and the prevalence of the disease both among the global population and among individual ethnic groups. In this paper, we describe 12 cases of arginine vasopressin resistance caused by a new homozygous mutation p.R113C in AQP2 presented among the indigenous population of the Republic of Buryatia.
... The decrease in the number of functioning nephrons in patients with acute or chronic kidney disease forces the remaining nephrons to excrete a larger proportion of the total solute load. Despite the impairment in concentrating ability, patients with acute or chronic kidney disease do not usually develop polyuria because the glomerular filtration rate is substantially reduced, and urine osmolality is usually isosmotic or only slightly hypoosmotic to plasma.114 Drug-induced NDISymptoms as a result of lithium toxicity are observed as early as 8 weeks after treatment with lithium carbonate. ...
Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1/25,000 population. Central DI (CDI), better now referred to as AVP‐deficiency, is the most common form of DI resulting from deficiency of the hormone arginine vasopressin (AVP) from the pituitary. The less common nephrogenic DI (NDI) or AVP‐resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP‐secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease‐causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. While the c‐AMP/PKA pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional c‐AMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurement of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice due to their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, while NDI requires the management of any underlying diseases, removal of offending drugs, and in some cases administration of diuretics. Better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents which are under clinical trial. This article is protected by copyright. All rights reserved.
... A second pivotal role for lysosomes in the kidney is related to the regulation of water and electrolyte homeostasis. Water reabsorption in the collecting duct relies on the vasopressin-dependent exocytosis of intracellular vesicles containing the water channel aquaporin 2 (AQP2) at the luminal surface of principal cells, thereby increasing water permeability [2]. Then, apical AQP2 is constitutively internalized by the endosomal system and is either recycled or targeted for lysosomal degradation to finely tune the amount of AQP2 available for water transport [3]. ...
... Then, apical AQP2 is constitutively internalized by the endosomal system and is either recycled or targeted for lysosomal degradation to finely tune the amount of AQP2 available for water transport [3]. The antidiuretic hormone vasopressin is crucial to regulate AQP2 retention on the apical membrane [2]. Activation of the vasopressin type 2 receptor (V2R) leads to a cytosolic increase in cAMP that stimulates protein kinase A (PKA) to phosphorylate AQP2. ...
... Activation of the vasopressin type 2 receptor (V2R) leads to a cytosolic increase in cAMP that stimulates protein kinase A (PKA) to phosphorylate AQP2. This signaling pathway leads to apical fusion and longer retention of AQP2-containing intracellular vesicles on the plasma membrane, thereby increasing the water permeability of the apical membrane [2]. ...
Lysosomes are acidic Ca2+ storage organelles that actively generate local Ca2+ signaling events to regulate a plethora of cell functions. Here, we characterized lysosomal Ca2+ signals in mouse renal collecting duct (CD) cells and we assessed their putative role in aquaporin 2 (AQP2)-dependent water reabsorption. Bafilomycin A1 and ML-SA1 triggered similar Ca2+ oscillations, in the absence of extracellular Ca2+, by alkalizing the acidic lysosomal pH or activating the lysosomal cation channel mucolipin 1 (TRPML1), respectively. TRPML1-dependent Ca2+ signals were blocked either pharmacologically or by lysosomes’ osmotic permeabilization, thus indicating these organelles as primary sources of Ca2+ release. Lysosome-induced Ca2+ oscillations were sustained by endoplasmic reticulum (ER) Ca2+ content, while bafilomycin A1 and ML-SA1 did not directly interfere with ER Ca2+ homeostasis per se. TRPML1 activation strongly increased AQP2 apical expression and depolymerized the actin cytoskeleton, thereby boosting water flux in response to an hypoosmotic stimulus. These effects were strictly dependent on the activation of the Ca2+/calcineurin pathway. Conversely, bafilomycin A1 led to perinuclear accumulation of AQP2 vesicles without affecting water permeability. Overall, lysosomal Ca2+ signaling events can be differently decoded to modulate Ca2+-dependent cellular functions related to the dock/fusion of AQP2-transporting vesicles in principal cells of the CD.
... Other drugs have been demonstrated to stimulate AQP2 migration to the luminal membrane by a cAMP-dependent mechanism such as PGE2 and rolupram or by AVP-and cAMP-independent mechanisms such as simvastatin, sildenafil, and metformin. These drugs might be promising when combined to mitigate the concentrating defect [53]. Targeting AQP2 regulation is the most promising therapeutic development. ...
Saving body water by optimal reabsorption of water filtered by the kidney leading to excretion of urine with concentrations of solutes largely above that of plasma allowed vertebrate species to leave the aquatic environment to live on solid ground. Filtered water is reabsorbed for 70% and 20% by proximal tubules and thin descending limbs of Henle, respectively. These two nephron segments express the water channel aquaporin-1 located along both apical and basolateral membranes. In the proximal tubule, the paracellular pathway accounts for at least 30% of water reabsorption, and the tight-junction core protein claudin-2 plays a key role in this permeability. The ascending limb of Henle and the distal convoluted tubule are impermeant to water and are responsible for urine dilution. The water balance is adjusted along the collecting system, i.e. connecting tubule and the collecting duct, under the control of arginine-vasopressin (AVP). AVP is synthesized by the hypothalamus and released in response to an increase in extracellular osmolality or stimulation of baroreceptors by decreased blood pressure. In response to AVP, aquaporin-2 water channels stored in subapical intracellular vesicles are translocated to the apical plasma membrane and raise the water permeability of the collecting system. The basolateral step of water reabsorption is mediated by aquaporin-3 and -4, which are constitutively expressed. Drugs targeting water transport include classical diuretics, which primarily inhibit sodium transport; the new class of SGLT2 inhibitors, which promotes osmotic diuresis and the non-peptidic antagonists of the V2 receptor, which are pure aquaretic drugs. Disturbed water balance includes diabetes insipidus and hyponatremias. Diabetes insipidus is characterized by polyuria and polydipsia. It is either related to a deficit in AVP secretion called central diabetes insipidus that can be treated by AVP analogs or to a peripheral defect in AVP response called nephrogenic diabetes insipidus. Diabetes insipidus can be either of genetic origin or acquired. Hyponatremia is a common disorder most often related to free water excess relying on overstimulated or inappropriate AVP secretion. The assessment of blood volume is key for the diagnosis and treatment of hyponatremia, which can be classified as hypo-, eu-, or hypervolemic.
... Interestingly, treatment with statins reduced urine output by increasing urinary concentration through inhibition of the small GTPases RhoA (Li et al., 2011;Procino et al., 2011). The approved pharmacologic therapy used to reduce polyuria consists of thiazide diuretics, Amiloride, a potassium-sparing agent or indomethacin, a prostaglandin inhibitor (Milano et al., 2017;Priya et al., 2021). ...
Renal collecting duct principal cells play a key role in controlling body water balance. Principal cells express the water channels AQP2, AQP3, and AQP4 that mediate renal water reabsorption. AQP3 and AQP4 are expressed at the basolateral membrane constitutively. Conversely, AQP2 is localized in intracellular vesicles and translocates to the plasma membrane under vasopressin action. Stimulation with vasopressin activates the cAMP/PKA signal transduction pathway that induces the redistribution of AQP2 from an intracellular pool to the apical plasma membrane. AQP2 trafficking and function depend on multiple post-translational modifications. Moreover, several proteins control different steps activated by the vasopressin stimulation that triggers the redistribution of the AQP2 vesicles. A-kinase anchoring proteins (AKAPs) together with phosphodiesterases and adenylate cyclases play crucial roles in modulating local changes of cAMP. Soluble N-ethylmaleimide sensitive fusion factor attachment protein receptors (SNARE), cytoskeletal proteins, and the small GTPases of the Rho family regulate the fusion and the endocytotic retrieval of AQP2 vesicles. Abnormal vasopressin signaling and altered AQP2 expression or trafficking can lead to disorders characterized by deregulated mechanisms controlling water homeostasis. This review provides updated data on the molecular signals regulating vasopressin-induced AQP2 trafficking in health and disease.
... Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by insensitivity of the distal nephron and collecting duct to the antidiuretic action of AVP and a consequent reduction in the ability of the kidneys to concentrate the urine, possibly leading to severe dehydration and electrolyte imbalance (1). In about 90% of cases, X-linked mutations in the vasopressin type 2 receptor (AVPR2) gene are responsible for the disease (2,3). ...
... Current approaches to the treatment of congenital NDI consist of reducing urine output. However, standard therapy using thiazide diuretics can only partially decrease urine output (1). ...
Congenital nephrogenic diabetes insipidus (NDI) is a rare disease that causes polydipsia and polyuria, and there are currently no effective treatments for most cases, particularly severe ones. The present report describes the case of a 1-yr-5-mo-old male patient with partial congenital NDI who was successfully treated with oral disintegrating 1-deamino-8-D-arginine vasopressin (DDAVP). The patient presented with poor weight gain and polydipsia (fluid, 1.5 L/d) and received a diagnosis of NDI after genetic analysis revealed an AVPR2 mutation (c.383A>C, p.Y128S). His water-restricted urine osmolality increased from 360 mOsm/kg/H2O to 667 mOsm/kg/H2O after subcutaneous AVP injection, indicating that he had some urine concentrating ability. Oral disintegrating DDAVP therapy was started at 360 µg/d with hydrochlorothiazide and increased to 720 µg/d without any adverse effects. A 30% decrease in urine output and water intake was followed by an increase in body weight. The present study is the first to report the effectiveness and safety of oral disintegrating DDAVP in a patient with partial congenital NDI due to an AVPR2 gene mutation. The severity of NDI at which DDAVP therapy is the most effective remains to be determined.
