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Advances in Experimental Medicine and... 2017Disruption of water and electrolyte balance is frequently encountered in clinical medicine. Regulating water metabolism is critically important. Diabetes insipidus (DI)... (Review)
Review
Disruption of water and electrolyte balance is frequently encountered in clinical medicine. Regulating water metabolism is critically important. Diabetes insipidus (DI) presented with excessive water loss from the kidney is a major disorder of water metabolism. To understand the molecular and cellular mechanisms and pathophysiology of DI and rationales of clinical management of DI is important for both research and clinical practice. This chapter will first review various forms of DI focusing on central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI ) . This is followed by a discussion of regulatory mechanisms underlying CDI and NDI , with a focus on the regulatory axis of vasopressin, vasopressin receptor 2 (V2R ) and the water channel molecule, aquaporin 2 (AQP2 ). The clinical manifestation, diagnosis and management of various forms of DI will also be discussed with highlights of some of the latest therapeutic strategies that are developed from in vitro experiments and animal studies.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidiuretic Agents; Aquaporin 2; Deamino Arginine Vasopressin; Diabetes Insipidus; Disease Models, Animal; Gene Expression Regulation; Humans; Kidney; Phosphodiesterase Inhibitors; Protein Isoforms; Receptors, Vasopressin; Vasopressins; Water; Water-Electrolyte Balance
PubMed: 28258576
DOI: 10.1007/978-94-024-1057-0_14 -
Experientia Supplementum (2012) 2019Body fluid homeostasis is essential for normal life. In the maintenance of water balance, the most important factor and regulated process is the excretory function of... (Review)
Review
Body fluid homeostasis is essential for normal life. In the maintenance of water balance, the most important factor and regulated process is the excretory function of the kidneys. The kidneys are capable to compensate not only the daily fluctuations of water intake but also the consequences of fluid loss (respiration, perspiration, sweating, hemorrhage). The final volume and osmolality of the excreted urine is set in the collecting duct via hormonal regulation. The hormone of water conservation is the vasopressin (AVP), and a large volume of urine is produced and excreted in the absence of AVP secretion or if AVP is ineffective in the kidneys. The aquaporin-2 water channel (AQP2) is expressed in the principal cells, and it plays an essential role in the reabsorption of water in the collecting ducts via type 2 vasopressin receptor (V2R)-mediated mechanism. If neural or hormonal regulation fails to operate the normal function of AVP-V2R-AQP2 system, it can result in various diseases such as diabetes insipidus (DI) or nephrogenic syndrome of inappropriate diuresis (NSIAD). The DI is characterized by excessive production of hyposmotic urine ("insipidus" means tasteless) due to the inability of the kidneys to concentrate urine. In this chapter, we focus and discuss the pathophysiology of nephrogenic DI (NDI) and the potential therapeutic interventions in the light of the current experimental data.
Topics: Aquaporin 2; Diabetes Insipidus, Nephrogenic; Humans; Receptors, Vasopressin; Water-Electrolyte Balance
PubMed: 31588538
DOI: 10.1007/978-3-030-25905-1_15 -
Current Hypertension Reports Jan 2015Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other... (Review)
Review
Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other physiologic functions including glucose metabolism, cardiovascular homeostasis, bone metabolism, and cognitive behavior. AVP receptor antagonists are now available and currently approved to treat hyponatremia. There is a great deal of interest in exploring the potential benefits that these drugs may play in blocking AVP-mediated effects in other organ systems. The purpose of this report is to provide an update on the expanding role of AVP receptor antagonists and what disease states these drugs may eventually be used for.
Topics: Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Humans; Hypertension; Receptors, Vasopressin
PubMed: 25604388
DOI: 10.1007/s11906-014-0510-4 -
Vitamins and Hormones 2020V2 vasopressin receptor (V2R) is a member of the G protein-coupled receptor (GPCR) family in which many disease-causing mutations have been identified and thus generated... (Review)
Review
V2 vasopressin receptor (V2R) is a member of the G protein-coupled receptor (GPCR) family in which many disease-causing mutations have been identified and thus generated much interest. Loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI) whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The mechanisms underlying a V2R loss-of-function can be theoretically classified as either protein expression, localization (ER retention) or functional disorders. Functional analyses have revealed however that these mechanisms are likely to be complex. Strikingly, V2R mutations at the same site can result in opposite phenotypes, e.g., R137H and R137L/C cause NDI and NSIAD, respectively. These findings support the notion that the constitutive activation of GPCRs might be often associated with their instability and denaturation. Thus, functional analysis of disease-causing V2R mutations may not only reveal potential new treatment strategies using pharmacochaperones for NDI and inverse agonists for NSIAD, but also provide a greater understanding of the physiological functions of GPCRs and highlight the new paradigms, i.e., biased agonism and protean agonism.
Topics: Diabetes Insipidus, Nephrogenic; Humans; Mutation; Receptors, Vasopressin
PubMed: 32138955
DOI: 10.1016/bs.vh.2019.08.012 -
American Journal of Physiology. Renal... Jan 2024Tolvaptan, a vasopressin antagonist selective for the V2-subtype vasopressin receptor (V2R), is widely used in the treatment of hyponatremia and autosomal-dominant...
Tolvaptan, a vasopressin antagonist selective for the V2-subtype vasopressin receptor (V2R), is widely used in the treatment of hyponatremia and autosomal-dominant polycystic kidney disease (ADPKD). Its effects on signaling in collecting duct cells have not been fully characterized. Here, we perform RNA-seq in a collecting duct cell line (mpkCCD). The data show that tolvaptan inhibits the expression of mRNAs that were previously shown to be increased in response to vasopressin including aquaporin-2, but also reveals mRNA changes that were not readily predictable and suggest off-target actions of tolvaptan. One such action is activation of the MAPK kinase (ERK1/ERK2) pathway. Prior studies have shown that ERK1/ERK2 activation is essential in the regulation of a variety of cellular and physiological processes and can be associated with cell proliferation. In immunoblotting experiments, we demonstrated that ERK1/ERK2 phosphorylation in mpkCCD cells was significantly reduced by vasopressin, in contrast to the increases seen in non-collecting-duct cells overexpressing V2R in prior studies. We also found that tolvaptan has a strong effect to increase ERK1/ERK2 phosphorylation in the presence of vasopressin and that tolvaptan's effect to increase ERK1/ERK2 phosphorylation is absent in mpkCCD cells in which both protein kinase A (PKA)-catalytic subunits have been deleted. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and is not due to an off-target effect of tolvaptan. We conclude that in cells expressing V2R at endogenous levels: ) vasopressin decreases ERK1/ERK2 activation; ) in the presence of vasopressin, tolvaptan increases ERK1/ERK2 activation; and ) these effects are PKA-dependent. Vasopressin is a key hormone that regulates the function of the collecting duct of the kidney. ERK1 and ERK2 are enzymes that play key roles in physiological regulation in all cells. The authors used collecting duct cell cultures to investigate the effects of vasopressin and the vasopressin receptor antagonist tolvaptan on ERK1 and ERK2 phosphorylation and activation.
Topics: Tolvaptan; Receptors, Vasopressin; Phosphorylation; MAP Kinase Signaling System; Kidney; Antidiuretic Hormone Receptor Antagonists; Vasopressins
PubMed: 37916285
DOI: 10.1152/ajprenal.00124.2023 -
Molecular and Cellular Endocrinology Jan 2023Nephrogenic diabetes insipidus is defined as an inability to concentrate urine due to a complete or partial alteration of the renal tubular response to arginine... (Review)
Review
Nephrogenic diabetes insipidus is defined as an inability to concentrate urine due to a complete or partial alteration of the renal tubular response to arginine vasopressin hormone, resulting in excessive diluted urine excretion. Hereditary forms are caused by molecular defects in the genes encoding either of the two main renal effectors of the arginine vasopressin pathway: the AVPR2 gene, which encodes for the type 2 vasopressin receptor, or the AQP2 gene, which encodes for the water channel aquaporin-2. About 90% of cases of nephrogenic diabetes insipidus result from loss-of-function variants in the AVPR2 gene, which are inherited in a X-linked recessive manner. The remaining 10% of cases result from loss-of-function variants in the AQP2 gene, which can be inherited in either a recessive or a dominant manner. The main symptoms of the disease are polyuria, chronic dehydration and hypernatremia. These symptoms usually occur in the first year of life, although some patients present later. Diagnosis is based on abnormal response in urinary osmolality after water restriction and/or administration of exogenous vasopressin. Treatment involves ensuring adequate water intake on demand, possibly combined with thiazide diuretics, non-steroidal anti-inflammatory drugs, and a low-salt and protein diet. In this review, we provide an update on current understanding of the molecular basis of inherited nephrogenic insipidus diabetes.
Topics: Humans; Aquaporin 2; Arginine Vasopressin; Diabetes Insipidus, Nephrogenic; Mutation; Receptors, Vasopressin
PubMed: 36460218
DOI: 10.1016/j.mce.2022.111825 -
Vitamins and Hormones 2020In mammals, three subtypes of V-receptors have been identified in the kidney. The effects of vasopressin, a hormone synthesized in the hypothalamus, are triggered by... (Review)
Review
In mammals, three subtypes of V-receptors have been identified in the kidney. The effects of vasopressin, a hormone synthesized in the hypothalamus, are triggered by three distinct receptor isoforms: V2, V1a, and V1b. Stimulation of V2-receptors regulates urine osmotic concentration by increasing sodium reabsorption in the thick ascending limb of the loop of Henle and enhancing osmotic permeability of the epithelium cells in the collecting duct. Stimulation of V1a-receptors inhibits renal sodium reabsorption and induces natriuresis, comparable to the effect of the diuretic furosemide, in the thick ascending limb of the loop of Henle. Stimulation of V1b-receptors induces potassium secretion in the final parts of the distal segments and initial parts of the collecting ducts. In this review, we discuss the role of vasopressin and its interaction with V-receptor subtypes in natriuresis and for stabilizing the physicochemical parameters of the internal environment and water-salt homeostasis in humans. A better understanding of these systems and their regulation is necessary to facilitate identification of additional system components and mechanisms, clarify their contribution during various normal and pathological functional states, and suggest novel strategies for the development of therapeutic interventions.
Topics: Humans; Kidney; Receptors, Vasopressin; Renal Elimination; Renal Reabsorption; Sodium
PubMed: 32138950
DOI: 10.1016/bs.vh.2019.08.013 -
Vitamins and Hormones 2020Vasopressin is a peptide hormone produced in the hypothalamus and released from the posterior pituitary. Secretion of vasopressin is followed by activation of its... (Review)
Review
Vasopressin is a peptide hormone produced in the hypothalamus and released from the posterior pituitary. Secretion of vasopressin is followed by activation of its receptors V1a, V1b, and V2 throughout the body. Each receptor type is responsible for a specific function of vasopressin. For example, V1a receptor activation triggers vasoconstriction, V1b receptor is responsible for modulation of mood and behavior, and V2 receptor induces water reabsorption in the kidney. Vasopressin is known to regulate blood pressure, blood osmolality, and blood volume. The effects of V1a and V2 receptors can be amplified when vasopressin is secreted in excessive amounts, and this condition may be experienced by patients undergoing a disease or stress. In pathological conditions such as stroke, traumatic brain injury, subarachnoid hemorrhage, liver disease, and other diseases, vasopressin can exacerbate brain edema. Oversecretion of vasopressin unleashes deleterious pathways leading to hyponatremia and brain edema. This book chapter describes important mechanisms and pathways linking vasopressin and brain edema triggered by various conditions.
Topics: Brain Edema; Humans; Receptors, Vasopressin; Signal Transduction; Vasopressins
PubMed: 32138953
DOI: 10.1016/bs.vh.2019.08.015 -
Annals of Nutrition & Metabolism 2018Diabetic nephropathy has become the most common cause of chronic kidney disease (CKD). Despite the progress accomplished in therapy, the prevalence of renal disorders... (Review)
Review
BACKGROUND
Diabetic nephropathy has become the most common cause of chronic kidney disease (CKD). Despite the progress accomplished in therapy, the prevalence of renal disorders remains high. Some modifiable factors driving the increase in incidence of CKD, in diabetes and other settings, might have been overlooked. Consistent evidence supports a role for vasopressin, hydration state, and urine concentration in kidney health.
SUMMARY
Plasma vasopressin is elevated in diabetes, even if metabolic control is good. Several epidemiological studies have pointed to a positive association between markers of vasopressin secretion (24-h fluid intake, urine volume, plasma copeptin concentration) and renal function decline in both the community and populations at high risk of CKD, namely, diabetic patients. Research involving animal models also supports a critical causal role of the V2 receptor antidiuretic effects of vasopressin in the early signs of kidney disease associated with type 1 or type 2 diabetes. Key Messages: Data supporting the detrimental effects of chronic vasopressin action on the kidney is consistent in animal models and human observational studies. Since vasopressin secretion can be modulated by water intake, and its actions by selective receptor antagonists, the vasopressin-hydration system could be a potential therapeutic target for the prevention and treatment of diabetic nephropathy. Intervention studies are needed to examine the relevance of lifestyle or pharmacological interventions.
Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Drinking; Glycopeptides; Humans; Randomized Controlled Trials as Topic; Receptors, Vasopressin; Vasopressins
PubMed: 29925069
DOI: 10.1159/000488124 -
Handbook of Clinical Neurology 2021Vasopressin is the key hormone involved in water conservation and regulation of water balance, essential for life. In the renal collecting duct, vasopressin binds to the... (Review)
Review
Vasopressin is the key hormone involved in water conservation and regulation of water balance, essential for life. In the renal collecting duct, vasopressin binds to the V2 receptor, increasing water permeability through activation of aquaporin-2 redistribution to the luminal membrane. This mechanism promotes rapid water reabsorption, important for immediate survival; however, only recently it has become clear that long-term adverse effects are associated with alterations of the vasopressin-aquaporin-2 pathway, leading to several syndromes associated with water balance disorders. The kidney resistance to the vasopressin action may cause severe dehydration for patients and, conversely, nonosmotic release of vasopressin is associated with water retention and increasing the circulatory blood volume. This chapter discusses the relevance of the altered vasopressin-aquaporin-2 pathway in some diseases associated with water balance disorders, including congenital nephrogenic diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The emerging picture suggests that targeting the vasopressin-AQP2 axis can provide therapeutic benefits in those patients.
Topics: Aquaporin 2; Diabetes Insipidus, Nephrogenic; Humans; Mutation; Receptors, Vasopressin; Vasopressins
PubMed: 34238461
DOI: 10.1016/B978-0-12-820683-6.00018-X