RARE DISEASE
Arginine vasopressin resistance
Arginine vasopressin resistance
Arginine vasopressin resistance
Synonyms: Nephrogenic diabetes insipidus
Synonyms: Nephrogenic diabetes insipidus
Synonyms: Nephrogenic diabetes insipidus
Drug discovery
2
drugs
With orphan designations
Overview
Arginine Vasopressin Resistance (AVP-R) is a renal disorder characterized by impaired kidney response to vasopressin (AVP), leading to excessive dilute urine output (polyuria) and compensatory thirst. Causes include genetic mutations (AVPR2 or AQP2), lithium toxicity, chronic kidney disease, and electrolyte imbalances. Diagnosis involves urine osmolality, serum electrolytes, and water deprivation testing. Management focuses on hydration, sodium restriction, thiazide diuretics, and NSAIDs to reduce urine volume [1][2][5][6].
Burden
Acute risks: Severe dehydration, hypernatremia, seizures, and coma if untreated [5][8][12].
Chronic complications: Developmental delays in children, renal damage, and reduced quality of life due to frequent urination [6][8][12].
Healthcare utilization: Requires lifelong monitoring, electrolyte management, and specialized care for hereditary cases [5][8][13].
Therapies
Hydration: Adequate free water intake to prevent dehydration [2][6][11].
Pharmacotherapy: Thiazide diuretics (hydrochlorothiazide) + NSAIDs to reduce urine output; low-salt/protein diets [2][6][13].
Underlying cause management: Discontinuing lithium (if applicable), correcting electrolyte imbalances [2][6][13].
Categories: rare genetic diseases, rare renal diseases
Research Papers
762 drug discovery papers about Arginine vasopressin resistance, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
762 drug discovery papers about Arginine vasopressin resistance, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-02 | Arginine vasopressin as the primary vasopressor in high-risk patients undergoing major non-cardiac surgery: A propensity-matched hemodynamic analysis.
Arginine vasopressin (AVP) is used as an adjunct to catecholamine vasopressors, but its role as a sole agent in high-risk non-cardiac surgery remains poorly defined. To characterize the integrated hemodynamic effects of AVP when used as the primary intraoperative vasopressor. In a propensity-matched physiological analysis, high-risk patients receiving AVP as the sole intraoperative vasopressor were matched to contemporaneous controls managed with catecholamine-based vasopressors. Serial hemodynamic data were analyzed, including arterial pressure, cardiac index, central venous pressure (CVP), venous return determinants, efficiency measures, and intraoperative fluid administration. Fifteen AVP-treated patients were matched to 13 controls, with all covariates balanced (SMDs <0.10). Mean AVP infusion rate was 0.023 (0.005) IU min-1. AVP patients received lower intraoperative fluids (p = 0.03) and had reduced net positive fluid balance (p = 0.02). Mean arterial pressure targets were maintained in both groups (AVP: 72-78 mmHg; controls: 70-76 mmHg). Cardiac index remained preserved with AVP (2.2-2.5 L min-1 m-2), comparable to controls (2.1-2.4 L min-1 m-2), despite lower CVP (AVP: 6-7 mmHg vs. 8-10 mmHg), consistent with effective recruitment of stressed volume and preserved cardiac function. Resistance to venous return remained stable over time, with no between-group differences (p > 0.05). AVP-treated patients demonstrated patterns consistent with improved circulatory efficiency compared with controls. In high-risk non-cardiac surgery, AVP-based hemodynamic management was associated with stable circulatory dynamics, preserved venous return, and reduced fluid exposure. These findings provide a physiological rationale for considering AVP as an alternative hemodynamic strategy in selected surgical patients.
2025-03-27 | Wnt-5a ameliorates sepsis-induced downregulation of renal AQP2 via the calcineurin signaling pathway.
Aquaporin 2 (AQP2), a vasopressin-sensitive water channel in the renal collecting ducts, maintains body water homeostasis. Sepsis reduces AQP2 and vasopressin receptor 2 (V2R) levels, contributing to acute kidney injury. In a heritable nephrogenic diabetes insipidus mouse model with V2R mutation, Wnt-5a, a ligand for frizzled receptors (Fzds), enhances AQP2 expression and translocation through calcium/calmodulin/calcineurin signaling. However, the mechanism by which Wnt-5a reduces sepsis-induced AQP2 inhibition remains unclear. We assessed this mechanism and whether Wnt-5a alleviates sepsis-induced downregulation of renal AQP2. Our study used in vitro and in vivo approaches. To study AQP2 trafficking, lipopolysaccharide (LPS) was applied to mouse inner medullary collecting duct 3 (mIMCD3) cells in vitro; subsequently, phosphorylated AQP2 and apical AQP2 expression as well as calcineurin activity and its upstream regulators (endogenous Wnt-5a, Fzds, and intracellular calcium intensity) were examined. In vivo, cecal ligation and puncture (CLP) mice were used to assess AQP2 levels and urine osmolality as indicators of urinary concentration. In mIMCD3 cells, LPS application was associated with reduced V2R expression, a vasopressin-irreversible reduction in AQP2, and increased Fzds turnover and Wnt-5a-stimulated intracellular calcium, enhancing calcineurin signaling. Subsequent application of Wnt-5a to LPS-exposed mIMCD3 cells prevented AQP2 reduction. Moreover, it increased phosphorylated AQP2 at residue Ser269 (Ser269-pAQP2) and decreased at Ser261-pAQP2 without affecting Ser256-pAQP2. These effects were reversed by the calcineurin inhibitor cyclosporin A. In CLP mice, Wnt-5a injection was associated with increased renal AQP2 and urine osmolality. Wnt-5a attenuates sepsis-induced AQP2 downregulation through the calcineurin signaling pathway.
2024-10-01 | 12227 The Battle Between Central And Nephrogenic Diabetes Insipidus
Abstract Disclosure: A.A. Luzuriaga Chavez: None. J.P. Hidalgo: None. A. Rao: None. N. Patel: None. Diabetes insipidus (DI) is a rare disorder characterized by excessive polyuria and polydipsia. The two main types include central diabetes insipidus (CDI), which results from antidiuretic hormone (ADH) deficiency and nephrogenic diabetes insipidus (NDI), defined by ADH resistance in the renal tubules. It can be challenging to distinguish between different types of DI in a critically ill patient. A 68-year-old female with a past medical history of hypertension, bipolar disorder came to the ER for complaints of chills and shortness of breath. She was transferred to the intensive care unit (ICU) for septic shock secondary to pneumonia and left pleural effusion. A chest tube was placed with improvement in her breathing and she was transferred out of the ICU. Four days later, the patient developed altered mental status, fevers and ICU was reconsulted due to concern for meningitis. A lumbar puncture was done with negative results but the brain MRI revealed ischemic sites involving both medial parietal cortices extending into both occipital poles, consistent with acute ischemia. Furthermore, the patient developed an increased urine output of 200ml per hour with a negative balance of 2.7L, increased sodium of 150, serum osmolality of 313 and urine osmolality of 196. The patient received desmopressin 1 mcg q 6 hrs with the persistence of hypernatremia. Upon further questioning, the patient had been on lithium therapy in the past for bipolar disorder. Amiloride 2.5mg BID was added to the treatment regimen. The patient’s hypernatremia and urine output improved and she was discharged on both amiloride and desmopressin to follow up for dose adjustments as needed. DI has a prevalence of 1 in 25000. Acquired CDI secondary to lesions in the hypophysis or hypothalamus highlights the major role of the central nervous system in regulating water homeostasis. This case report describes CDI developing after a stroke. Ischemia can cause hypoperfusion of osmoreceptors in the hypothalamus and posterior pituitary. Lithium can be frequently associated with NDI, usually seen in 20 to 40% of patients. Different mechanisms of action include lithium interference in renal collecting tubules by increasing cAMP in response to ADH and down-regulation of aquaporin-2 expression, which is accepted to be reversible with the cessation of the therapy. However, long-term treatment with lithium likely results in permanent NDI. Our patient had a history of lithium therapy which contributed to the development of symptoms of NDI and responded to a combination of desmopressin and amiloride. The successful therapy enforces the diagnosis of both a central and a peripheral pathology. Central and nephrogenic DI, despite stemming from distinct underlying causes, may concurrently manifest in critically ill patients. This case report emphasizes the need for physicians to evaluate for multiple causes of DI in a patient with water disturbances. Presentation: 6/1/2024
2024-10-01 | Can Acetylation of Lysine 282 of Aquaporin 3 Improve Urinary Concentration in Mice with Lithium-Induced Nephrogenic Diabetes Insipidus?
Background: The principal cell basolateral water channel AQP3 is decreased in lithium-induced nephrogenic diabetes insipidus (NDI) and AQP3-null mice have an NDI phenotype with polyuria. We previously identified a novel AQP3 post-translational modification, acetylation of lysine 282 (K282), which we found to affect protein membrane localization. We hypothesized that lysine acetylation of AQP3 may improve the polyuria in NDI. Methods: Mice with homozygous mutations of AQP3 K282R (deacetylated mimetic, R) or K282Q (acetylated mimetic, Q) were compared to wild type K282 (WT) mice. Male and female 11–16-week-old mice were fed a lithium-containing diet or control diet (40 mmol LiCl or NaCl/kg dry food) for 14 days (n = 5-6/group). 24 h food and water intake, urine flow, and plasma osmolality at day 14 were measured. Results: On the control diet, food intake (WT 6.8±0.3, Q 6.3± 0.7, R 6.2±0.8 g/day, p=0.9), water intake (WT 3.6±0.3, Q 3.4±0.3, R 4.0±0.2, p=0.9), and urine flow (WT 1.4±0.4, Q 1.3±0.3, R 1.3±0.3 ml/day, p = 0.9) were similar among the male mice. The control diet females also had similar food intake (WT 6.4±0.4, Q 6.2±0.3, R 6.2±0.7 g/day, p = 0.38), water intake (WT 3.2±0.3, Q 3.4±0.2, R 3.9±0.4, p=0.9), and urine flow (WT 0.2±0.1, Q 0.5±0.1, R 0.5 ±0.2 ml/day, p=0.9). As expected, the lithium-diet fed mice developed polyuria/polydipsia. In male mice, food intake was lower in the WT (5.5±0.3 g/day) than Q and R (7.4±0.6 and 7.0±0.4 g/day, p = 0.02); however, R mutant mice had greater urine flow (12.8 ± 1.2 ml/day) than WT (4.8±0.5 ml/day) and Q mice (7.9±1.8 ml/day, p=0.0004). The females ate similar amounts of lithium diet (WT 6.4±0.3, Q 6.4±0.5, R 5.4±0.5 g/day, p=0.99) but urine flow was enhanced in Q (9.8±1.4 ml/day) and R (8.5±1.3 ml/day) mice compared to WT (4.8±0.5 ml/day, p=0.02). Water intake was significantly increased in all lithium-fed mice regardless of genotype (p<0.001). There were no significant effects of treatment or genotype on plasma osmolality among the groups. Conclusion: Contrary to our hypothesis, AQP3 acetylation- and deacetylation-mimetics had worsened polyuria in lithium-induced NDI, suggesting that K282 is an important regulatory site for AQP3 function perhaps independent of acetylation status. Funding: NIDDK Support
2024-07-14 | Arginine vasopressin deficiency: diagnosis, management and the relevance of oxytocin deficiency.
Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution.
small molecules
2026-08-03 | Nephrogenic Diabetes Insipidus Presenting with Hypokalemic Paralysis in an Adolescent with Primary Sjögren's Syndrome: A Case Report.
Diabetes insipidus (DI) is a rare disorder characterized by polyuria, polydipsia, and dilute urine. Nephrogenic diabetes insipidus (NDI) secondary to distal renal tubular acidosis (dRTA) in primary Sjögren's syndrome (pSS) is exceedingly rare in children. A 16-year-old girl presented with hypokalemic paralysis (potassium 1.89 mmol/L), polyuria (>5 L/day),and growth retardation (height 141 cm, <3rd percentile). Laboratory studies revealed dRTA with secondary NDI. Autoimmune workup confirmed pSS. A systematic literature review identified only five similar pediatric cases. Initial management with hydrochlorothiazide exacerbated hypokalemia and precipitated hypochloremic metabolic alkalosis. Switching to amiloride combined with glucocorticoids and potassium supplementation normalized electrolytes, reduced urine output to 1.5 L/day, and resulted in catch-up growth at the 6-month follow-up. This case highlights the pathophysiologic cascade of pSS-related dRTA causing secondary NDI and underscores the importance of early recognition and tailored diuretic selection in adolescents.
2026-07-06 | Proteomic profile of urinary extracellular vesicles from rats with lithium-induced nephrogenic diabetes insipidus.
Lithium (Li) salts have been widely used to treat bipolar disorder and unipolar depression for more than 50 years. However, up to 40% of people taking Li develop Nephrogenic Diabetes Insipidus (NDI). NDI is associated with cellular remodeling in the rodent kidney collecting duct and reduced aquaporin-2. Patients taking Li for more than 10-20 years are at risk of chronic kidney disease, which ultimately can lead to end-stage renal disease, hemodialysis, transplantation, or death. The purpose of this study was to investigate whether the rat urinary proteome can be used as an indicator of Li-induced changes in kidney. Extracellular vesicles were isolated from the urine of rats treated with Li for 2 or 4 weeks followed by LC-MS/MS analysis. The results showed a limited correlation between protein changes in urine and kidney. However, the urine contained markers of mitochondrial dysfunction. The cytoskeletal protein, Keratin 8, showed a tendency to be higher in the urine and was greatly increased in collecting duct principal cells in response to Li, suggesting a potential role in cellular remodeling. Canonical Histone H4 was increased in the urine, and was observed in the nuclei of collecting duct principal and intercalated cells following Li. Moreover, Histone H4 positive cells co-localized with the proliferation marker, PCNA. This correlates with the known increased proliferation in the collecting duct in response to Li. Thus, replication-dependent Histone H4 is a possible urinary marker for the Li induced cellular remodeling of the collecting duct.
2026-06-25 | Infant Nephrogenic Diabetes Insipidus: Challenges Leading to Delayed Management.
Nephrogenic diabetes insipidus (NDI) is a rare, potentially life-threatening renal tubular disorder characterized by a decreased ability to concentrate urine due to antidiuretic hormone (ADH) resistance, leading to significant free water loss. The congenital form, most often caused by X-linked mutations in the AVPR2 gene, typically presents in early infancy. Due to its rarity and nonspecific clinical features in young children, such as failure to thrive, vomiting, and excessive fluid intake, diagnostic delays are common, especially in centers with limited prior experience in managing NDI. We report a case of a 17-month-old male infant presenting with severe hypernatremia, dehydration, vomiting, and failure to thrive. Initial clinical findings, a partial response to desmopressin, and absent neurohypophysis signaling on MRI suggested central diabetes insipidus (CDI), leading to a delay in the correct diagnosis. However, persistent polyuria, despite escalating desmopressin doses, prompted reconsideration. Genetic testing confirmed a pathogenic AVPR2 mutation (c.541C > T, p. Arg181Cys), establishing the diagnosis of congenital NDI. Therapeutic management included thiazide diuretics, NSAIDs, and dietary sodium restriction, resulting in slow and gradual clinical stabilization. This case highlights several diagnostic challenges, such as misinterpreting partial desmopressin response and MRI results. It emphasizes the importance of systematic diagnostic algorithms for infants with polyuria and early genetic testing when clinical presentations lack clarity. We aim to share our clinical experience and the pitfalls encountered while managing a patient with NDI and contribute to earlier and more effective recognition and treatment of this rare condition, preventing the development of life-threatening complications.
2026-06-05 | Diagnosis and Management of Acute and Chronic Lithium-Associated Nephrotoxicity.
Lithium remains a mainstay of therapy for bipolar disease and refractory depression with future potential for expanded use on the basis of novel data demonstrating its immunomodulatory and neuroprotective effects. This drug accumulates intracellularly via sodium transport pathways, and its effects on complex cellular signaling mechanisms, including glycogen synthase kinase-3 β inhibition, form the basis of its therapeutic efficacy and toxicity. Increased intracellular levels disrupt cellular processes and trigger injury via mitochondrial dysfunction and oxidative stress. Lithium has a narrow therapeutic index and causes dose-dependent nephrotoxicity. A tubulointerstitial pattern of kidney injury is typical; however, lithium can rarely cause glomerular injury as well. An acute rise in serum lithium levels can result in severe volume depletion from lithium-induced natriuresis and aquaresis and cause AKI. Changes in kidney function and various drug interactions can acutely affect serum lithium levels further increasing the risk of toxicity. Arginine vasopressin resistance is the most common complication of chronic lithium use and can be an early manifestation. CKD occurs after a longer latency of over 10 years with a variable slope of GFR decline. Progression to ESKD is relatively low but is affected by the presence of other nephrotoxic risk factors. Epithelial sodium channel blockers such as amiloride can be helpful in mitigating lithium nephrotoxicity by reducing cellular accumulation. Hypercalcemia secondary to lithium-induced hyperparathyroidism is associated with a higher risk of nephrolithiasis and CKD progression. Kidney microcystic changes are common in lithium-induced CKD, and distal renal tubular acidosis can also be seen. Using the lowest effective lithium dose, close monitoring of kidney function and serum lithium levels and early diagnosis of lithium nephrotoxicity is critical in preventing irreversible kidney injury. The decision to discontinue lithium is challenging, and the benefits versus risks must be carefully weighed. This comprehensive review provides a pathogenetic basis and practical clinical framework for diagnosis and management of lithium nephrotoxicity.
2026-05-01 | Notch signaling and mTOR complex 1 play opposing roles in regulation of kidney collecting duct cell type plasticity
Intercalated cell (IC) types are intermingled among principal cell (PC) types along the kidney collecting duct segments. The ratio of PC to IC types increases along the cortico-medullary axis to ensure water, electrolyte and pH homeostasis. Previous studies have shown that Notch signaling via Hes1 is necessary for maintenance of PC types without which they convert to IC types resulting in diminished urine concentrating capacity. Here we sought to determine the molecular mechanisms by which Hes1 prevents cell type conversion and the physiological conditions that trigger PC to IC conversions. The molecular signature of the transitional cell (TC) state during the PC to IC conversion was determined by single cell RNA-sequencing of adult wild type and Hes1-deficient mouse kidney samples enriched for epithelial cells of the loop of Henle, distal nephron and collecting duct segments. Based on the TC molecular signature we determined that the mechanistic target of rapamycin complex 1 (mTORC1) activity is increased in Hes1-deficient PCs of adult kidneys and tested if mTORC1 activity regulates collecting duct cell type plasticity. Conditional inactivation of Raptor reduced mTORC1 activity, decreased IC specific gene expression in adult mouse kidneys and resulted in production of more acidic urine, while activation of mTORC1 in PCs triggered expression of IC specific genes and conversion to IC state. Interestingly, inhibiting mTORC1 by conditionally inactivating Raptor rescues the deficiency in PCs and urine concentration defect observed in Hes1 conditional knock out adult mouse kidneys. Collectively, our results indicate that Notch signaling and mTORC1 activity play opposing roles in promoting PC versus IC state within the adult kidney collecting ducts to ensure water and pH homeostasis. It is likely that certain physiological stressors, medications and diets that activate mTORC1 and/or suppress Notch signaling promote the conversion of PCs to ICs. While transient and limited PC to IC conversion is perhaps part of the adaptive cell type plasticity necessary for water and electrolyte balance, chronic and excessive PC to IC conversions likely underlie acquired forms of nephrogenic diabetes insipidus. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
gene therapies
2019-06-03 | Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype
Dysregulated arousal often accompanies neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder. Recently, we have found that adolescent homozygous Brattleboro (Hom) rats, which contain a mutation in the arginine vasopressin (AVP) gene, exhibit lower behavioral arousal than their heterozygous (Het) littermates in the open field test. This hypoaroused phenotype could be due to loss of AVP in magnocellular cells that supply AVP to the peripheral circulation and project to limbic structures or parvocellular cells that regulate the stress axis and other central targets. Alternatively, hypoarousal could be a side effect of diabetes insipidus - polydipsia and polyuria seen in Hom rats due to loss of AVP facilitation of water reabsorption in the kidney. We developed a viral-rescue approach to "cure" magnocellular AVP cells of their Brattleboro mutation. Infusion of a recombinant adeno-associated virus (rAAV) containing a functional Avp gene and promoter (rAAV-AVP) rescued AVP within magnocellular cells and fiber projections of the paraventricular nucleus of the hypothalamus (PVN) of male and female adolescent Hom rats. Furthermore, water intake was markedly reduced, ameliorating the symptoms of diabetes insipidus. In contrast, open field activity was unaffected. These findings indicate that the hyporaoused phenotype of adolescent Hom rats is not due to the loss of AVP function in magnocellular cells or a side effect of diabetes insipidus, but favors the hypothesis that central, parvocellular AVP mechanisms underlie the regulation of arousal during adolescence.
2009-11-17 | Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice.
The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developing kidney. Mice lacking Mib1 in the renal collecting duct displayed increased urinary production, decreased urinary osmolality, progressive hydronephrosis, sodium wasting, and a severe urinary concentrating defect manifested as nephrogenic diabetes insipidus. Histological analysis revealed a diminished number of principal cells and corresponding increase in the number of intercalated cells. Transgenic overexpression of Notch intracellular domain reversed the altered cellular composition of mutant renal collecting duct, with principal cells occupying the entire region. Our data demonstrate that Notch signaling is required for the development of the mammalian renal collecting duct and principal cell differentiation and indicate that pathway dysregulation may contribute to distal renal tubular disorders.
2009-05-18 | Involvement of the V2 Vasopressin Receptor in Adaptation to Limited Water Supply
Mammals adapted to a great variety of habitats with different accessibility to water. In addition to changes in kidney morphology, e.g. the length of the loops of Henle, several hormone systems are involved in adaptation to limited water supply, among them the renal-neurohypophysial vasopressin/vasopressin receptor system. Comparison of over 80 mammalian V2 vasopressin receptor (V2R) orthologs revealed high structural and functional conservation of this key component involved in renal water reabsorption. Although many mammalian species have unlimited access to water there is no evidence for complete loss of V2R function indicating an essential role of V2R activity for survival even of those species. In contrast, several marsupial V2R orthologs show a significant increase in basal receptor activity. An increased vasopressin-independent V2R activity can be interpreted as a shift in the set point of the renal-neurohypophysial hormone circuit to realize sufficient water reabsorption already at low hormone levels. As found in other desert mammals arid-adapted marsupials show high urine osmolalities. The gain of basal V2R function in several marsupials may contribute to the increased urine concentration abilities and, therefore, provide an advantage to maintain water and electrolyte homeostasis under limited water supply conditions.
2008-07-24 | Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 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/DeltaF) 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/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) 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.
2005-08-18 | Diabetes Insipidus in Mice with a Mutation in Aquaporin-2
Congenital nephrogenic diabetes insipidus (NDI) is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI.
oligonucleotides
2022-12-10 | Ribosomal s6 kinase (RSK) is a mediator of aquaporin 2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib
Abstract Vasopressin (VP) activates PKA, resulting in phosphorylation and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2 membrane trafficking with a phosphorylation pattern similar to VP, but without increasing PKA activity. Here, we identify the ribosomal s6 kinase (RSK) as the final mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. We found that RSK was expressed in medullary principal cells in rat kidneys. RSK inhibition with BI-D1870 or siRNA blocked erlotinib-induced AQP2 S256 phosphorylation and membrane trafficking. CRISPR-generated RSK knockout cells failed to show increased S256 phosphorylation in response to erlotinib. Like PKA, RSK was able to phosphorylate AQP2 S256 in vitro . Stimulation of PDK1, a known activator of RSK, caused AQP2 S256 phosphorylation and membrane accumulation similar to erlotinib and VP. We conclude that RSK is the terminal kinase phosphorylating AQP2 at S256 upon EGFR inhibition by erlotinib.
2021-10-04 | Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus.
MicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression. Selective ablation of Dicer in AQP2-expressing cells (DicerAQP2Cre+ mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice. The mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in DicerAQP2Cre+ mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in DicerAQP2Cre+ mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409-3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in DicerAQP2Cre+ mice, resulting in decreased RNA Pol II association. Novel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression.
2018-06-21 | The Emerging Role of microRNAs in Aquaporin Regulation
Aquaporins (AQPs) are membrane channels widely distributed in human tissues. AQPs are essential for water and energy homeostasis being involved in a broad range of pathophysiological processes such as edema, brain injury, glaucoma, nephrogenic diabetes insipidus, salivary and lacrimal gland dysfunction, cancer, obesity and related metabolic complications. Compelling evidence indicates that AQPs are targets for therapeutic intervention with potential broad application. Nevertheless, efficient AQP modulators have been difficult to find due to either lack of selectivity and stability, or associated toxicity that hamper in vivo studies. MicroRNAs (miRNAs) are naturally occurring small non-coding RNAs that regulate post-transcriptional gene expression and are involved in several diseases. Recent identification of miRNAs as endogenous modulators of AQP expression provides an alternative approach to target these proteins and opens new perspectives for therapeutic applications. This mini-review compiles the current knowledge of miRNA interaction with AQPs highlighting miRNA potential for regulation of AQP-based disorders.
2016-03-28 | Vasopressin Regulates Extracellular Vesicle Uptake by Kidney Collecting Duct Cells
Extracellular vesicles (ECVs) facilitate intercellular communication along the nephron, with the potential to change the function of the recipient cell. However, it is not known whether this is a regulated process analogous to other signaling systems. We investigated the potential hormonal regulation of ECV transfer and report that desmopressin, a vasopressin analogue, stimulated the uptake of fluorescently loaded ECVs into a kidney collecting duct cell line (mCCDC11) and into primary cells. Exposure of mCCDC11 cells to ECVs isolated from cells overexpressing microRNA-503 led to downregulated expression of microRNA-503 target genes, but only in the presence of desmopressin. Mechanistically, ECV entry into mCCDC11 cells required cAMP production, was reduced by inhibiting dynamin, and was selective for ECVs from kidney tubular cells. In vivo, we measured the urinary excretion and tissue uptake of fluorescently loaded ECVs delivered systemically to mice before and after administration of the vasopressin V2 receptor antagonist tolvaptan. In control-treated mice, we recovered 2.5% of administered ECVs in the urine; tolvaptan increased recovery five-fold and reduced ECV deposition in kidney tissue. Furthermore, in a patient with central diabetes insipidus, desmopressin reduced the excretion of ECVs derived from glomerular and proximal tubular cells. These data are consistent with vasopressin-regulated uptake of ECVs in vivo We conclude that ECV uptake is a specific and regulated process. Physiologically, ECVs are a new mechanism of intercellular communication; therapeutically, ECVs may be a vehicle by which RNA therapy could be targeted to specific cells for the treatment of kidney disease.
2015-02-23 | Myosin light chain kinase controls voltage-dependent calcium channels in vascular smooth muscle.
The Ca(2+)-dependent kinase myosin light chain kinase (MLCK) is the activator of smooth muscle contraction. In addition, it has been reported to be involved in Ca(2+) channel regulation in cultured cells, and we previously showed that the MLCK inhibitor ML-7 decreases arginine vasopressin (AVP)-induced Ca(2+) influx in rat aorta. This study was designed to investigate whether MLCK is involved in Ca(2+) regulation in resistance artery smooth muscle cell, which plays a major role in the control of blood pressure. As ML compounds were shown to have off-target effects, MLCK was downregulated by transfection with a small interfering RNA targeting MLCK (MLCK-siRNA) in rat small resistance mesenteric artery (RMA) and in the rat embryonic aortic cell line A7r5. Noradrenaline-induced contraction and Ca(2+) signal were significantly depressed in MLCK-siRNA compared to scramble-siRNA-transfected RMA. Contraction and Ca(2+) signal induced by high KCl and voltage-activated Ca(2+) current were also significantly decreased in MLCK-siRNA-transfected RMA, suggesting that MLCK depletion modifies voltage-operated Ca(2+) channels. KCl- and AVP-induced Ca(2+) signals and voltage-activated Ca(2+) current were decreased in MLCK-depleted A7r5 cells. Eventually, real-time quantitative PCR analysis indicated that in A7r5, MLCK controlled mRNA expression of CaV1.2 (L-type) and CaV3.1 (T-type) voltage-dependent Ca(2+) channels. Our results suggest that MLCK controls the transcription of voltage-dependent Ca(2+) channels in vascular smooth muscle cells.
other
2025-10-01 | Tonicity Matures the Collecting Ducts of the Kidneys
Background: Organ maturation is a fundamental question in biology. Building mature organoids is also essential for regenerative medicine. We have developed kidney organoids induced from mouse and human pluripotent stem cells (Taguchi et al. Cell Stem Cell 2014; Taguchi and Nishinakamura. Cell Stem Cell 2017; Tanigawa et al. Nat. Commun. 2022). However, these kidney organoids are still immature. Previous studies have reported that endocrine hormones, shear stress, and metabolic substrates promote kidney maturation (Uchimura et al. Cell Reports 2020; Homan et al. Nat. Methods 2019; Wang et al. Cell Stem Cell 2022). Our motivation here was to uncover a new maturation program. Methods: We hypothesized that high tonicity, one of the unique characteristics of the kidney medulla, would mature the collecting ducts (CDs). We cultured mouse and human ureteric buds, which are the precursors of CDs, at high tonicity by adding sodium chloride to the culture media, and investigated their maturity. For disease modeling, we established iPSC lines harboring one of the mutations of nephrogenic diabetes insipidus (NDI) and induced mature human CD organoids from these cell lines. Results: Mouse CD organoids matured at high tonicity in terms of morphology, genetic profile, and physiological function. Our scRNA-seq analysis revealed that a broad spectrum of genes, including transcription factors, signaling molecules, and transporters, were upregulated by tonicity and that these genes accounted for approximately half of the maturation markers of the medullary CDs. This process was mainly dependent on the transcription factor NFAT5 (nuclear factor of activated T cells 5). Based on these findings, we have established a maturation protocol for human CD organoids. Human CDs also morphologically and transcriptionally matured and acquired vasopressin responsiveness at high tonicity. Furthermore, the mature CD organoids induced from iPSC lines with a mutation that causes NDI lost their responsiveness to vasopressin, whereas the control organoids responded to vasopressin with AQP2 clearly localized on the apical membrane. Conclusion: High tonicity is a driving force for mammalian kidney maturation, not only for urine concentration. Our study uncovers a novel principle of organ maturation triggered by environmental cues and offers a promising way to maximize the potential of organoids for disease modeling and therapy development. Funding: Government Support – Non-U.S.
proteins
2026-08-02 | Arginine vasopressin as the primary vasopressor in high-risk patients undergoing major non-cardiac surgery: A propensity-matched hemodynamic analysis.
Arginine vasopressin (AVP) is used as an adjunct to catecholamine vasopressors, but its role as a sole agent in high-risk non-cardiac surgery remains poorly defined. To characterize the integrated hemodynamic effects of AVP when used as the primary intraoperative vasopressor. In a propensity-matched physiological analysis, high-risk patients receiving AVP as the sole intraoperative vasopressor were matched to contemporaneous controls managed with catecholamine-based vasopressors. Serial hemodynamic data were analyzed, including arterial pressure, cardiac index, central venous pressure (CVP), venous return determinants, efficiency measures, and intraoperative fluid administration. Fifteen AVP-treated patients were matched to 13 controls, with all covariates balanced (SMDs <0.10). Mean AVP infusion rate was 0.023 (0.005) IU min-1. AVP patients received lower intraoperative fluids (p = 0.03) and had reduced net positive fluid balance (p = 0.02). Mean arterial pressure targets were maintained in both groups (AVP: 72-78 mmHg; controls: 70-76 mmHg). Cardiac index remained preserved with AVP (2.2-2.5 L min-1 m-2), comparable to controls (2.1-2.4 L min-1 m-2), despite lower CVP (AVP: 6-7 mmHg vs. 8-10 mmHg), consistent with effective recruitment of stressed volume and preserved cardiac function. Resistance to venous return remained stable over time, with no between-group differences (p > 0.05). AVP-treated patients demonstrated patterns consistent with improved circulatory efficiency compared with controls. In high-risk non-cardiac surgery, AVP-based hemodynamic management was associated with stable circulatory dynamics, preserved venous return, and reduced fluid exposure. These findings provide a physiological rationale for considering AVP as an alternative hemodynamic strategy in selected surgical patients.
2025-03-27 | Wnt-5a ameliorates sepsis-induced downregulation of renal AQP2 via the calcineurin signaling pathway.
Aquaporin 2 (AQP2), a vasopressin-sensitive water channel in the renal collecting ducts, maintains body water homeostasis. Sepsis reduces AQP2 and vasopressin receptor 2 (V2R) levels, contributing to acute kidney injury. In a heritable nephrogenic diabetes insipidus mouse model with V2R mutation, Wnt-5a, a ligand for frizzled receptors (Fzds), enhances AQP2 expression and translocation through calcium/calmodulin/calcineurin signaling. However, the mechanism by which Wnt-5a reduces sepsis-induced AQP2 inhibition remains unclear. We assessed this mechanism and whether Wnt-5a alleviates sepsis-induced downregulation of renal AQP2. Our study used in vitro and in vivo approaches. To study AQP2 trafficking, lipopolysaccharide (LPS) was applied to mouse inner medullary collecting duct 3 (mIMCD3) cells in vitro; subsequently, phosphorylated AQP2 and apical AQP2 expression as well as calcineurin activity and its upstream regulators (endogenous Wnt-5a, Fzds, and intracellular calcium intensity) were examined. In vivo, cecal ligation and puncture (CLP) mice were used to assess AQP2 levels and urine osmolality as indicators of urinary concentration. In mIMCD3 cells, LPS application was associated with reduced V2R expression, a vasopressin-irreversible reduction in AQP2, and increased Fzds turnover and Wnt-5a-stimulated intracellular calcium, enhancing calcineurin signaling. Subsequent application of Wnt-5a to LPS-exposed mIMCD3 cells prevented AQP2 reduction. Moreover, it increased phosphorylated AQP2 at residue Ser269 (Ser269-pAQP2) and decreased at Ser261-pAQP2 without affecting Ser256-pAQP2. These effects were reversed by the calcineurin inhibitor cyclosporin A. In CLP mice, Wnt-5a injection was associated with increased renal AQP2 and urine osmolality. Wnt-5a attenuates sepsis-induced AQP2 downregulation through the calcineurin signaling pathway.
2024-10-01 | 12227 The Battle Between Central And Nephrogenic Diabetes Insipidus
Abstract Disclosure: A.A. Luzuriaga Chavez: None. J.P. Hidalgo: None. A. Rao: None. N. Patel: None. Diabetes insipidus (DI) is a rare disorder characterized by excessive polyuria and polydipsia. The two main types include central diabetes insipidus (CDI), which results from antidiuretic hormone (ADH) deficiency and nephrogenic diabetes insipidus (NDI), defined by ADH resistance in the renal tubules. It can be challenging to distinguish between different types of DI in a critically ill patient. A 68-year-old female with a past medical history of hypertension, bipolar disorder came to the ER for complaints of chills and shortness of breath. She was transferred to the intensive care unit (ICU) for septic shock secondary to pneumonia and left pleural effusion. A chest tube was placed with improvement in her breathing and she was transferred out of the ICU. Four days later, the patient developed altered mental status, fevers and ICU was reconsulted due to concern for meningitis. A lumbar puncture was done with negative results but the brain MRI revealed ischemic sites involving both medial parietal cortices extending into both occipital poles, consistent with acute ischemia. Furthermore, the patient developed an increased urine output of 200ml per hour with a negative balance of 2.7L, increased sodium of 150, serum osmolality of 313 and urine osmolality of 196. The patient received desmopressin 1 mcg q 6 hrs with the persistence of hypernatremia. Upon further questioning, the patient had been on lithium therapy in the past for bipolar disorder. Amiloride 2.5mg BID was added to the treatment regimen. The patient’s hypernatremia and urine output improved and she was discharged on both amiloride and desmopressin to follow up for dose adjustments as needed. DI has a prevalence of 1 in 25000. Acquired CDI secondary to lesions in the hypophysis or hypothalamus highlights the major role of the central nervous system in regulating water homeostasis. This case report describes CDI developing after a stroke. Ischemia can cause hypoperfusion of osmoreceptors in the hypothalamus and posterior pituitary. Lithium can be frequently associated with NDI, usually seen in 20 to 40% of patients. Different mechanisms of action include lithium interference in renal collecting tubules by increasing cAMP in response to ADH and down-regulation of aquaporin-2 expression, which is accepted to be reversible with the cessation of the therapy. However, long-term treatment with lithium likely results in permanent NDI. Our patient had a history of lithium therapy which contributed to the development of symptoms of NDI and responded to a combination of desmopressin and amiloride. The successful therapy enforces the diagnosis of both a central and a peripheral pathology. Central and nephrogenic DI, despite stemming from distinct underlying causes, may concurrently manifest in critically ill patients. This case report emphasizes the need for physicians to evaluate for multiple causes of DI in a patient with water disturbances. Presentation: 6/1/2024
2024-10-01 | Can Acetylation of Lysine 282 of Aquaporin 3 Improve Urinary Concentration in Mice with Lithium-Induced Nephrogenic Diabetes Insipidus?
Background: The principal cell basolateral water channel AQP3 is decreased in lithium-induced nephrogenic diabetes insipidus (NDI) and AQP3-null mice have an NDI phenotype with polyuria. We previously identified a novel AQP3 post-translational modification, acetylation of lysine 282 (K282), which we found to affect protein membrane localization. We hypothesized that lysine acetylation of AQP3 may improve the polyuria in NDI. Methods: Mice with homozygous mutations of AQP3 K282R (deacetylated mimetic, R) or K282Q (acetylated mimetic, Q) were compared to wild type K282 (WT) mice. Male and female 11–16-week-old mice were fed a lithium-containing diet or control diet (40 mmol LiCl or NaCl/kg dry food) for 14 days (n = 5-6/group). 24 h food and water intake, urine flow, and plasma osmolality at day 14 were measured. Results: On the control diet, food intake (WT 6.8±0.3, Q 6.3± 0.7, R 6.2±0.8 g/day, p=0.9), water intake (WT 3.6±0.3, Q 3.4±0.3, R 4.0±0.2, p=0.9), and urine flow (WT 1.4±0.4, Q 1.3±0.3, R 1.3±0.3 ml/day, p = 0.9) were similar among the male mice. The control diet females also had similar food intake (WT 6.4±0.4, Q 6.2±0.3, R 6.2±0.7 g/day, p = 0.38), water intake (WT 3.2±0.3, Q 3.4±0.2, R 3.9±0.4, p=0.9), and urine flow (WT 0.2±0.1, Q 0.5±0.1, R 0.5 ±0.2 ml/day, p=0.9). As expected, the lithium-diet fed mice developed polyuria/polydipsia. In male mice, food intake was lower in the WT (5.5±0.3 g/day) than Q and R (7.4±0.6 and 7.0±0.4 g/day, p = 0.02); however, R mutant mice had greater urine flow (12.8 ± 1.2 ml/day) than WT (4.8±0.5 ml/day) and Q mice (7.9±1.8 ml/day, p=0.0004). The females ate similar amounts of lithium diet (WT 6.4±0.3, Q 6.4±0.5, R 5.4±0.5 g/day, p=0.99) but urine flow was enhanced in Q (9.8±1.4 ml/day) and R (8.5±1.3 ml/day) mice compared to WT (4.8±0.5 ml/day, p=0.02). Water intake was significantly increased in all lithium-fed mice regardless of genotype (p<0.001). There were no significant effects of treatment or genotype on plasma osmolality among the groups. Conclusion: Contrary to our hypothesis, AQP3 acetylation- and deacetylation-mimetics had worsened polyuria in lithium-induced NDI, suggesting that K282 is an important regulatory site for AQP3 function perhaps independent of acetylation status. Funding: NIDDK Support
2024-07-14 | Arginine vasopressin deficiency: diagnosis, management and the relevance of oxytocin deficiency.
Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution.
small molecules
2026-08-03 | Nephrogenic Diabetes Insipidus Presenting with Hypokalemic Paralysis in an Adolescent with Primary Sjögren's Syndrome: A Case Report.
Diabetes insipidus (DI) is a rare disorder characterized by polyuria, polydipsia, and dilute urine. Nephrogenic diabetes insipidus (NDI) secondary to distal renal tubular acidosis (dRTA) in primary Sjögren's syndrome (pSS) is exceedingly rare in children. A 16-year-old girl presented with hypokalemic paralysis (potassium 1.89 mmol/L), polyuria (>5 L/day),and growth retardation (height 141 cm, <3rd percentile). Laboratory studies revealed dRTA with secondary NDI. Autoimmune workup confirmed pSS. A systematic literature review identified only five similar pediatric cases. Initial management with hydrochlorothiazide exacerbated hypokalemia and precipitated hypochloremic metabolic alkalosis. Switching to amiloride combined with glucocorticoids and potassium supplementation normalized electrolytes, reduced urine output to 1.5 L/day, and resulted in catch-up growth at the 6-month follow-up. This case highlights the pathophysiologic cascade of pSS-related dRTA causing secondary NDI and underscores the importance of early recognition and tailored diuretic selection in adolescents.
2026-07-06 | Proteomic profile of urinary extracellular vesicles from rats with lithium-induced nephrogenic diabetes insipidus.
Lithium (Li) salts have been widely used to treat bipolar disorder and unipolar depression for more than 50 years. However, up to 40% of people taking Li develop Nephrogenic Diabetes Insipidus (NDI). NDI is associated with cellular remodeling in the rodent kidney collecting duct and reduced aquaporin-2. Patients taking Li for more than 10-20 years are at risk of chronic kidney disease, which ultimately can lead to end-stage renal disease, hemodialysis, transplantation, or death. The purpose of this study was to investigate whether the rat urinary proteome can be used as an indicator of Li-induced changes in kidney. Extracellular vesicles were isolated from the urine of rats treated with Li for 2 or 4 weeks followed by LC-MS/MS analysis. The results showed a limited correlation between protein changes in urine and kidney. However, the urine contained markers of mitochondrial dysfunction. The cytoskeletal protein, Keratin 8, showed a tendency to be higher in the urine and was greatly increased in collecting duct principal cells in response to Li, suggesting a potential role in cellular remodeling. Canonical Histone H4 was increased in the urine, and was observed in the nuclei of collecting duct principal and intercalated cells following Li. Moreover, Histone H4 positive cells co-localized with the proliferation marker, PCNA. This correlates with the known increased proliferation in the collecting duct in response to Li. Thus, replication-dependent Histone H4 is a possible urinary marker for the Li induced cellular remodeling of the collecting duct.
2026-06-25 | Infant Nephrogenic Diabetes Insipidus: Challenges Leading to Delayed Management.
Nephrogenic diabetes insipidus (NDI) is a rare, potentially life-threatening renal tubular disorder characterized by a decreased ability to concentrate urine due to antidiuretic hormone (ADH) resistance, leading to significant free water loss. The congenital form, most often caused by X-linked mutations in the AVPR2 gene, typically presents in early infancy. Due to its rarity and nonspecific clinical features in young children, such as failure to thrive, vomiting, and excessive fluid intake, diagnostic delays are common, especially in centers with limited prior experience in managing NDI. We report a case of a 17-month-old male infant presenting with severe hypernatremia, dehydration, vomiting, and failure to thrive. Initial clinical findings, a partial response to desmopressin, and absent neurohypophysis signaling on MRI suggested central diabetes insipidus (CDI), leading to a delay in the correct diagnosis. However, persistent polyuria, despite escalating desmopressin doses, prompted reconsideration. Genetic testing confirmed a pathogenic AVPR2 mutation (c.541C > T, p. Arg181Cys), establishing the diagnosis of congenital NDI. Therapeutic management included thiazide diuretics, NSAIDs, and dietary sodium restriction, resulting in slow and gradual clinical stabilization. This case highlights several diagnostic challenges, such as misinterpreting partial desmopressin response and MRI results. It emphasizes the importance of systematic diagnostic algorithms for infants with polyuria and early genetic testing when clinical presentations lack clarity. We aim to share our clinical experience and the pitfalls encountered while managing a patient with NDI and contribute to earlier and more effective recognition and treatment of this rare condition, preventing the development of life-threatening complications.
2026-06-05 | Diagnosis and Management of Acute and Chronic Lithium-Associated Nephrotoxicity.
Lithium remains a mainstay of therapy for bipolar disease and refractory depression with future potential for expanded use on the basis of novel data demonstrating its immunomodulatory and neuroprotective effects. This drug accumulates intracellularly via sodium transport pathways, and its effects on complex cellular signaling mechanisms, including glycogen synthase kinase-3 β inhibition, form the basis of its therapeutic efficacy and toxicity. Increased intracellular levels disrupt cellular processes and trigger injury via mitochondrial dysfunction and oxidative stress. Lithium has a narrow therapeutic index and causes dose-dependent nephrotoxicity. A tubulointerstitial pattern of kidney injury is typical; however, lithium can rarely cause glomerular injury as well. An acute rise in serum lithium levels can result in severe volume depletion from lithium-induced natriuresis and aquaresis and cause AKI. Changes in kidney function and various drug interactions can acutely affect serum lithium levels further increasing the risk of toxicity. Arginine vasopressin resistance is the most common complication of chronic lithium use and can be an early manifestation. CKD occurs after a longer latency of over 10 years with a variable slope of GFR decline. Progression to ESKD is relatively low but is affected by the presence of other nephrotoxic risk factors. Epithelial sodium channel blockers such as amiloride can be helpful in mitigating lithium nephrotoxicity by reducing cellular accumulation. Hypercalcemia secondary to lithium-induced hyperparathyroidism is associated with a higher risk of nephrolithiasis and CKD progression. Kidney microcystic changes are common in lithium-induced CKD, and distal renal tubular acidosis can also be seen. Using the lowest effective lithium dose, close monitoring of kidney function and serum lithium levels and early diagnosis of lithium nephrotoxicity is critical in preventing irreversible kidney injury. The decision to discontinue lithium is challenging, and the benefits versus risks must be carefully weighed. This comprehensive review provides a pathogenetic basis and practical clinical framework for diagnosis and management of lithium nephrotoxicity.
2026-05-01 | Notch signaling and mTOR complex 1 play opposing roles in regulation of kidney collecting duct cell type plasticity
Intercalated cell (IC) types are intermingled among principal cell (PC) types along the kidney collecting duct segments. The ratio of PC to IC types increases along the cortico-medullary axis to ensure water, electrolyte and pH homeostasis. Previous studies have shown that Notch signaling via Hes1 is necessary for maintenance of PC types without which they convert to IC types resulting in diminished urine concentrating capacity. Here we sought to determine the molecular mechanisms by which Hes1 prevents cell type conversion and the physiological conditions that trigger PC to IC conversions. The molecular signature of the transitional cell (TC) state during the PC to IC conversion was determined by single cell RNA-sequencing of adult wild type and Hes1-deficient mouse kidney samples enriched for epithelial cells of the loop of Henle, distal nephron and collecting duct segments. Based on the TC molecular signature we determined that the mechanistic target of rapamycin complex 1 (mTORC1) activity is increased in Hes1-deficient PCs of adult kidneys and tested if mTORC1 activity regulates collecting duct cell type plasticity. Conditional inactivation of Raptor reduced mTORC1 activity, decreased IC specific gene expression in adult mouse kidneys and resulted in production of more acidic urine, while activation of mTORC1 in PCs triggered expression of IC specific genes and conversion to IC state. Interestingly, inhibiting mTORC1 by conditionally inactivating Raptor rescues the deficiency in PCs and urine concentration defect observed in Hes1 conditional knock out adult mouse kidneys. Collectively, our results indicate that Notch signaling and mTORC1 activity play opposing roles in promoting PC versus IC state within the adult kidney collecting ducts to ensure water and pH homeostasis. It is likely that certain physiological stressors, medications and diets that activate mTORC1 and/or suppress Notch signaling promote the conversion of PCs to ICs. While transient and limited PC to IC conversion is perhaps part of the adaptive cell type plasticity necessary for water and electrolyte balance, chronic and excessive PC to IC conversions likely underlie acquired forms of nephrogenic diabetes insipidus. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
gene therapies
2019-06-03 | Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype
Dysregulated arousal often accompanies neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder. Recently, we have found that adolescent homozygous Brattleboro (Hom) rats, which contain a mutation in the arginine vasopressin (AVP) gene, exhibit lower behavioral arousal than their heterozygous (Het) littermates in the open field test. This hypoaroused phenotype could be due to loss of AVP in magnocellular cells that supply AVP to the peripheral circulation and project to limbic structures or parvocellular cells that regulate the stress axis and other central targets. Alternatively, hypoarousal could be a side effect of diabetes insipidus - polydipsia and polyuria seen in Hom rats due to loss of AVP facilitation of water reabsorption in the kidney. We developed a viral-rescue approach to "cure" magnocellular AVP cells of their Brattleboro mutation. Infusion of a recombinant adeno-associated virus (rAAV) containing a functional Avp gene and promoter (rAAV-AVP) rescued AVP within magnocellular cells and fiber projections of the paraventricular nucleus of the hypothalamus (PVN) of male and female adolescent Hom rats. Furthermore, water intake was markedly reduced, ameliorating the symptoms of diabetes insipidus. In contrast, open field activity was unaffected. These findings indicate that the hyporaoused phenotype of adolescent Hom rats is not due to the loss of AVP function in magnocellular cells or a side effect of diabetes insipidus, but favors the hypothesis that central, parvocellular AVP mechanisms underlie the regulation of arousal during adolescence.
2009-11-17 | Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice.
The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developing kidney. Mice lacking Mib1 in the renal collecting duct displayed increased urinary production, decreased urinary osmolality, progressive hydronephrosis, sodium wasting, and a severe urinary concentrating defect manifested as nephrogenic diabetes insipidus. Histological analysis revealed a diminished number of principal cells and corresponding increase in the number of intercalated cells. Transgenic overexpression of Notch intracellular domain reversed the altered cellular composition of mutant renal collecting duct, with principal cells occupying the entire region. Our data demonstrate that Notch signaling is required for the development of the mammalian renal collecting duct and principal cell differentiation and indicate that pathway dysregulation may contribute to distal renal tubular disorders.
2009-05-18 | Involvement of the V2 Vasopressin Receptor in Adaptation to Limited Water Supply
Mammals adapted to a great variety of habitats with different accessibility to water. In addition to changes in kidney morphology, e.g. the length of the loops of Henle, several hormone systems are involved in adaptation to limited water supply, among them the renal-neurohypophysial vasopressin/vasopressin receptor system. Comparison of over 80 mammalian V2 vasopressin receptor (V2R) orthologs revealed high structural and functional conservation of this key component involved in renal water reabsorption. Although many mammalian species have unlimited access to water there is no evidence for complete loss of V2R function indicating an essential role of V2R activity for survival even of those species. In contrast, several marsupial V2R orthologs show a significant increase in basal receptor activity. An increased vasopressin-independent V2R activity can be interpreted as a shift in the set point of the renal-neurohypophysial hormone circuit to realize sufficient water reabsorption already at low hormone levels. As found in other desert mammals arid-adapted marsupials show high urine osmolalities. The gain of basal V2R function in several marsupials may contribute to the increased urine concentration abilities and, therefore, provide an advantage to maintain water and electrolyte homeostasis under limited water supply conditions.
2008-07-24 | Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 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/DeltaF) 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/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) 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.
2005-08-18 | Diabetes Insipidus in Mice with a Mutation in Aquaporin-2
Congenital nephrogenic diabetes insipidus (NDI) is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI.
oligonucleotides
2022-12-10 | Ribosomal s6 kinase (RSK) is a mediator of aquaporin 2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib
Abstract Vasopressin (VP) activates PKA, resulting in phosphorylation and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2 membrane trafficking with a phosphorylation pattern similar to VP, but without increasing PKA activity. Here, we identify the ribosomal s6 kinase (RSK) as the final mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. We found that RSK was expressed in medullary principal cells in rat kidneys. RSK inhibition with BI-D1870 or siRNA blocked erlotinib-induced AQP2 S256 phosphorylation and membrane trafficking. CRISPR-generated RSK knockout cells failed to show increased S256 phosphorylation in response to erlotinib. Like PKA, RSK was able to phosphorylate AQP2 S256 in vitro . Stimulation of PDK1, a known activator of RSK, caused AQP2 S256 phosphorylation and membrane accumulation similar to erlotinib and VP. We conclude that RSK is the terminal kinase phosphorylating AQP2 at S256 upon EGFR inhibition by erlotinib.
2021-10-04 | Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus.
MicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression. Selective ablation of Dicer in AQP2-expressing cells (DicerAQP2Cre+ mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice. The mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in DicerAQP2Cre+ mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in DicerAQP2Cre+ mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409-3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in DicerAQP2Cre+ mice, resulting in decreased RNA Pol II association. Novel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression.
2018-06-21 | The Emerging Role of microRNAs in Aquaporin Regulation
Aquaporins (AQPs) are membrane channels widely distributed in human tissues. AQPs are essential for water and energy homeostasis being involved in a broad range of pathophysiological processes such as edema, brain injury, glaucoma, nephrogenic diabetes insipidus, salivary and lacrimal gland dysfunction, cancer, obesity and related metabolic complications. Compelling evidence indicates that AQPs are targets for therapeutic intervention with potential broad application. Nevertheless, efficient AQP modulators have been difficult to find due to either lack of selectivity and stability, or associated toxicity that hamper in vivo studies. MicroRNAs (miRNAs) are naturally occurring small non-coding RNAs that regulate post-transcriptional gene expression and are involved in several diseases. Recent identification of miRNAs as endogenous modulators of AQP expression provides an alternative approach to target these proteins and opens new perspectives for therapeutic applications. This mini-review compiles the current knowledge of miRNA interaction with AQPs highlighting miRNA potential for regulation of AQP-based disorders.
2016-03-28 | Vasopressin Regulates Extracellular Vesicle Uptake by Kidney Collecting Duct Cells
Extracellular vesicles (ECVs) facilitate intercellular communication along the nephron, with the potential to change the function of the recipient cell. However, it is not known whether this is a regulated process analogous to other signaling systems. We investigated the potential hormonal regulation of ECV transfer and report that desmopressin, a vasopressin analogue, stimulated the uptake of fluorescently loaded ECVs into a kidney collecting duct cell line (mCCDC11) and into primary cells. Exposure of mCCDC11 cells to ECVs isolated from cells overexpressing microRNA-503 led to downregulated expression of microRNA-503 target genes, but only in the presence of desmopressin. Mechanistically, ECV entry into mCCDC11 cells required cAMP production, was reduced by inhibiting dynamin, and was selective for ECVs from kidney tubular cells. In vivo, we measured the urinary excretion and tissue uptake of fluorescently loaded ECVs delivered systemically to mice before and after administration of the vasopressin V2 receptor antagonist tolvaptan. In control-treated mice, we recovered 2.5% of administered ECVs in the urine; tolvaptan increased recovery five-fold and reduced ECV deposition in kidney tissue. Furthermore, in a patient with central diabetes insipidus, desmopressin reduced the excretion of ECVs derived from glomerular and proximal tubular cells. These data are consistent with vasopressin-regulated uptake of ECVs in vivo We conclude that ECV uptake is a specific and regulated process. Physiologically, ECVs are a new mechanism of intercellular communication; therapeutically, ECVs may be a vehicle by which RNA therapy could be targeted to specific cells for the treatment of kidney disease.
2015-02-23 | Myosin light chain kinase controls voltage-dependent calcium channels in vascular smooth muscle.
The Ca(2+)-dependent kinase myosin light chain kinase (MLCK) is the activator of smooth muscle contraction. In addition, it has been reported to be involved in Ca(2+) channel regulation in cultured cells, and we previously showed that the MLCK inhibitor ML-7 decreases arginine vasopressin (AVP)-induced Ca(2+) influx in rat aorta. This study was designed to investigate whether MLCK is involved in Ca(2+) regulation in resistance artery smooth muscle cell, which plays a major role in the control of blood pressure. As ML compounds were shown to have off-target effects, MLCK was downregulated by transfection with a small interfering RNA targeting MLCK (MLCK-siRNA) in rat small resistance mesenteric artery (RMA) and in the rat embryonic aortic cell line A7r5. Noradrenaline-induced contraction and Ca(2+) signal were significantly depressed in MLCK-siRNA compared to scramble-siRNA-transfected RMA. Contraction and Ca(2+) signal induced by high KCl and voltage-activated Ca(2+) current were also significantly decreased in MLCK-siRNA-transfected RMA, suggesting that MLCK depletion modifies voltage-operated Ca(2+) channels. KCl- and AVP-induced Ca(2+) signals and voltage-activated Ca(2+) current were decreased in MLCK-depleted A7r5 cells. Eventually, real-time quantitative PCR analysis indicated that in A7r5, MLCK controlled mRNA expression of CaV1.2 (L-type) and CaV3.1 (T-type) voltage-dependent Ca(2+) channels. Our results suggest that MLCK controls the transcription of voltage-dependent Ca(2+) channels in vascular smooth muscle cells.
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2025-10-01 | Tonicity Matures the Collecting Ducts of the Kidneys
Background: Organ maturation is a fundamental question in biology. Building mature organoids is also essential for regenerative medicine. We have developed kidney organoids induced from mouse and human pluripotent stem cells (Taguchi et al. Cell Stem Cell 2014; Taguchi and Nishinakamura. Cell Stem Cell 2017; Tanigawa et al. Nat. Commun. 2022). However, these kidney organoids are still immature. Previous studies have reported that endocrine hormones, shear stress, and metabolic substrates promote kidney maturation (Uchimura et al. Cell Reports 2020; Homan et al. Nat. Methods 2019; Wang et al. Cell Stem Cell 2022). Our motivation here was to uncover a new maturation program. Methods: We hypothesized that high tonicity, one of the unique characteristics of the kidney medulla, would mature the collecting ducts (CDs). We cultured mouse and human ureteric buds, which are the precursors of CDs, at high tonicity by adding sodium chloride to the culture media, and investigated their maturity. For disease modeling, we established iPSC lines harboring one of the mutations of nephrogenic diabetes insipidus (NDI) and induced mature human CD organoids from these cell lines. Results: Mouse CD organoids matured at high tonicity in terms of morphology, genetic profile, and physiological function. Our scRNA-seq analysis revealed that a broad spectrum of genes, including transcription factors, signaling molecules, and transporters, were upregulated by tonicity and that these genes accounted for approximately half of the maturation markers of the medullary CDs. This process was mainly dependent on the transcription factor NFAT5 (nuclear factor of activated T cells 5). Based on these findings, we have established a maturation protocol for human CD organoids. Human CDs also morphologically and transcriptionally matured and acquired vasopressin responsiveness at high tonicity. Furthermore, the mature CD organoids induced from iPSC lines with a mutation that causes NDI lost their responsiveness to vasopressin, whereas the control organoids responded to vasopressin with AQP2 clearly localized on the apical membrane. Conclusion: High tonicity is a driving force for mammalian kidney maturation, not only for urine concentration. Our study uncovers a novel principle of organ maturation triggered by environmental cues and offers a promising way to maximize the potential of organoids for disease modeling and therapy development. Funding: Government Support – Non-U.S.
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Drug Discovery Landscape
2 orphan drug designations for Arginine vasopressin resistance.
2 orphan drug designations for Arginine vasopressin resistance.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
1-[12-(1 Carboxycyclopropyl) dodecyl] cyclopropane-1-carboxylic acid | small molecules | FDA | 2022-12-07 | — | NephroDI Therapeutics, Inc. |
1,1¿-(1, 12- Dodecanediyl)bis[cyclopropanecarboxamide] | small molecules | FDA | 2022-02-03 | — | NephroDI Therapeutics, Inc. |
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