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Scheinberg AR, Martin P, Turkeltaub JA. Terlipressin in the management of liver disease. Expert Opin Pharmacother 2023; 24:1665-1671. [PMID: 37535437 DOI: 10.1080/14656566.2023.2244427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/26/2023] [Accepted: 08/01/2023] [Indexed: 08/05/2023]
Abstract
INTRODUCTION Terlipressin is a synthetic vasopressin analog which has been recently approved in the United States by the Food and Drug Administration for the treatment of hepatorenal syndrome. Terlipressin stimulates vasopressin receptors located on the smooth muscle vasculature of the splanchnic circulation and renal tubules which results in splanchnic vasoconstriction with improved renal perfusion and antidiuretic activity, respectively. AREAS COVERED In this review, we discuss available data regarding the FDA approved use of terlipressin, safety, and tolerability, as well as highlight alternative uses in chronic liver disease currently still under investigation. EXPERT OPINION Terlipressin is more efficacious compared to other vasoactive agents including midodrine octreotide and norepinephrine in reversal of hepatorenal syndrome and improves short-term survival. Other potential applications of terlipressin's vasoconstrictor actions reported in the literature include management of variceal hemorrhage and other complications of portal hypertension.
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Affiliation(s)
- Andrew R Scheinberg
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Miami, FL, USA
| | - Paul Martin
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Miami, FL, USA
| | - Joshua A Turkeltaub
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Miami, FL, USA
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2
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Li N, Ying Y, Yang B. Aquaporins in Edema. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1398:281-287. [PMID: 36717501 DOI: 10.1007/978-981-19-7415-1_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
One of the most prevalent indications of water-electrolyte imbalance is edema. Aquaporins (AQPs) are a protein family that can function as water channels. Osmoregulation and body water homeostasis are dependent on the regulation of AQPs. Human kidneys contain nine AQPs, five of which have been demonstrated to have a role in body water balance: AQP1, AQP2, AQP3, AQP4, and AQP7. Water imbalance is connected with AQP dysfunction. Hyponatremia with elevated AQP levels can accompany edema, which can be caused by disorders with low effective circulating blood volume and systemic vasodilation, such as congestive heart failure (CHF), hepatic cirrhosis, or the syndrome of incorrect antidiuretic hormone secretion (SIADH). In CHF, upregulation of AQP2 expression and targeting is critical for water retention. AQP2 is also involved in aberrant water retention and the formation of ascites in cirrhosis of the liver. Furthermore, water retention and hyponatremia in SIADH are caused by increased expression of AQP2 in the collecting duct. Fluid restriction, demeclocycline, and vasopressin type-2 receptor antagonists are widely utilized to treat edema. The relationship between AQPs and edema is discussed in this chapter.
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Affiliation(s)
- Nannan Li
- School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yi Ying
- School of Basic Medical Sciences, Peking University, Beijing, China
| | - Baoxue Yang
- School of Basic Medical Sciences, Peking University, Beijing, China.
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Ala M, Mohammad Jafari R, Hajiabbasi A, Dehpour AR. Aquaporins and diseases pathogenesis: From trivial to undeniable involvements, a disease-based point of view. J Cell Physiol 2021; 236:6115-6135. [PMID: 33559160 DOI: 10.1002/jcp.30318] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 01/01/2023]
Abstract
Aquaporins (AQPs), as transmembrane proteins, were primarily identified as water channels with the ability of regulating the transmission of water, glycerol, urea, and other small-sized molecules. The classic view of AQPs involvement in therapeutic plan restricted them and their regulators into managing only a narrow spectrum of the diseases such as diabetes insipidus and the syndrome of inappropriate ADH secretion. However, further investigations performed, especially in the third millennium, has found that their cooperation in water transmission control can be manipulated to handle other burden-imposing diseases such as cirrhosis, heart failure, Meniere's disease, cancer, bullous pemphigoid, eczema, and Sjögren's syndrome.
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Affiliation(s)
- Moein Ala
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Razieh Mohammad Jafari
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Asghar Hajiabbasi
- Guilan Rheumatology Research Center, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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Li M, Li X, Zhang Y, Wu H, Zhou H, Ding X, Zhang X, Jin X, Wang Y, Yin X, Li C, Yang P, Xu H. Micropeptide MIAC Inhibits HNSCC Progression by Interacting with Aquaporin 2. J Am Chem Soc 2020; 142:6708-6716. [PMID: 32176498 DOI: 10.1021/jacs.0c00706] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Several important micropeptides encoded by noncoding RNAs have been identified in recent years; however, there have never been any reports of micropeptides in head and neck squamous cell carcinoma (HNSCC). Here we report the discovery and characterization of a human endogenous peptide named micropeptide inhibiting actin cytoskeleton (MIAC). Comprehensive analysis of the TCGA (The Cancer Genome Atlas) database (n = 500), clinical fresh samples (n = 94), and tissue microarrays (n = 60) revealed that lower MIAC expression is correlated with poor overall survival of HNSCC patients. Meanwhile, RNA-sequencing analysis of 9657 human tissues across 32 cancer types from TCGA cohorts found that MIAC is significantly associated with the progression of 5 other different tumors. Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. Collectively, the mechanism investigation and evaluation of MIAC activity in vivo and in vitro highlights that MIAC plays an important role in HNSCC tumorigenesis.
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Affiliation(s)
| | | | | | - Heming Wu
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, P. R. China
| | | | - Xu Ding
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Xiaomin Zhang
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, P. R. China
| | | | | | | | - Chencheng Li
- Nanjing Anji Biotechnology Co. Ltd., Nanjing, Jiangsu 210009, P. R. China
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Nakai M, Ogawa K, Takeda R, Ohara M, Kawagishi N, Izumi T, Umemura M, Ito J, Sho T, Suda G, Morikawa K, Sakamoto N. Increased serum C-reactive protein and decreased urinary aquaporin 2 levels are predictive of the efficacy of tolvaptan in patients with liver cirrhosis. Hepatol Res 2018; 48:E311-E319. [PMID: 28984014 DOI: 10.1111/hepr.12988] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 09/25/2017] [Accepted: 09/30/2017] [Indexed: 02/08/2023]
Abstract
AIM Water retention, hepatic ascites, and peripheral edema are significant problems in patients with liver cirrhosis (LC). Although furosemide and spironolactone are commonly used as treatment, they are often insufficient to treat hyponatremia and renal insufficiency in patients with LC. Tolvaptan (TVP) could provide an effective treatment alternative. However, predictive factors of a therapeutic response to TVP are unclear. Our aim was to examine clinical predictors of the response to TVP in patients with LC and water retention. METHODS Fifty-two patients were treated with TVP, with therapeutic effects judged by a decrease in body weight (≥2 kg) and increase in urinary volume (≥500 mL) within 7 days. Blood biochemical tests were carried out at baseline and post-treatment, including serum soluble CD14 (sCD14) and urinary aquaporin 2 (AQP2) levels. Clinical and laboratory predictive factors of a TVP response were evaluated by univariate and multivariate analyses. RESULTS The overall response to TVP was 55.8%. On univariate analyses, serum C-reactive protein (CRP) level, the neutrophil-to-lymphocyte ratio, urinary blood urea nitrogen, and urinary AQP2 were predictors of the TVP response, with only serum CRP retained on multivariate analysis. A higher serum sCD14 level was strongly associated with a non-response to TVP. A decrease in urinary AQP2 to undetectable level was associated with a response. CONCLUSION Tolvaptan provides a rapid and strong effect to improve water retention in patients with LC. Baseline serum sCD14 and CRP levels are useful predictors of a response to TVP, with a decrease in urinary AQP2 during treatment indicating an early response.
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Affiliation(s)
- Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Rei Takeda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Busk TM, Møller S, Pedersen EB, Gerbes A, Krag A, Peck-Radosavljevic M, Frankova S, Coenraad MJ, Bendtsen F. Aquaporin-2 excretion in hospitalized patients with cirrhosis: Relation to development of renal insufficiency and mortality. J Gastroenterol Hepatol 2017; 32:1087-1093. [PMID: 28092112 DOI: 10.1111/jgh.13641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/27/2016] [Accepted: 11/01/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Urinary aquaporin-2 (AQP2) is a parameter of water transport in the principal cells in the distal part of the nephron and involved in water retention in cirrhosis and may be a marker of renal function. The aim of the study was to evaluate AQP2 as a predictor of renal insufficiency and death in patients with cirrhosis. METHODS Urine samples from 199 patients (90 patients without organ failure [Group 1], 58 patients with organ failure excluding renal failure [Group 2], and 51 patients with organ failure including renal failure [Group 3]) from the CANONIC study were analyzed for urine AQP2 and urine osmolality. RESULTS There was no difference in AQP2 between the three groups. Urine osmolality was significantly lower in patients in Group 3 versus Group 1 and Group 2 (P = 0.0004). No relation was found between AQP2 and glomerular filtration rate or creatinine; however, AQP2 was a significant predictor of the development of renal insufficiency (P = 0.0485). In a univariate analysis, AQP2 was a significant predictor of 14 and 28-day survival, but this was not confirmed in multivariate analysis. CONCLUSIONS Aquaporin-2 was not associated with disease severity or markers of renal function but was a predictor for the development of renal insufficiency and death. Therefore, its future use as marker of renal insufficiency could be promising, but further research is needed before it can be considered a clinical useful tool.
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Affiliation(s)
- Troels M Busk
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Søren Møller
- Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Erling B Pedersen
- University Clinic of Nephrology and Hypertension, Aarhus University and Holstebro Hospital, Aarhus, Denmark
| | - Alexander Gerbes
- Liver Center Munich, Klinikum of the University, Ludwig Maximilian University of Munich, Munich, Germany
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Markus Peck-Radosavljevic
- Department of Gastroenterology and Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörtersee, Klagenfurt, Austria
| | - Sona Frankova
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Minneke J Coenraad
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
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Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites. J Gastroenterol 2016; 51:620-7. [PMID: 26610908 DOI: 10.1007/s00535-015-1143-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/28/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND The water channel aquaporin 2 (AQP2) at the apical membrane of renal collecting duct cells mediates water reabsorption. The expression of AQP2 at the apical membrane is tightly regulated by vasopressin and was quantitated by measurement of the urinary form by a recently developed ELISA. Tolvaptan, an antagonist of vasopressin type 2 receptor, inhibits water reabsorption in cirrhosis. The aim of this study was to determine the correlation between the pharmacological effect of tolvaptan and the dynamics of urinary AQP2 levels. METHODS Tolvaptan was administered to 41 cirrhotic patients with ascites unresponsive to standard diuretic therapy. Urinary excretion of AQP2 and urinary osmolarity were measured at the baseline and at 4, 8, and 24 h after administration of tolvaptan. RESULTS At the baseline, urinary AQP2/creatinine ratios were significantly higher in cirrhotic patients with ascites than in healthy controls (P < 0.0001). After administration of tolvaptan, urinary AQP2/creatinine ratios decreased by 45.0 % at 4 h and 77.0 % at 8 h. Similarly, urinary osmolarity decreased by 42.0 % at 4 h and 41.5 % at 8 h. Urinary AQP2 levels and urinary osmolarity significantly correlated at the baseline and at all time points after tolvaptan administration. The degree of the decrease in urinary AQP2 levels and degree of the decrease in urinary osmolarity correlated significantly at 4 h (r = 0.452, P = 0.009) and 8 h (r = 0.384, P = 0.030) after tolvaptan administration. CONCLUSIONS These results indicate that the vasopressin-AQP2 system plays a major role in fluid retention in cirrhosis and that the pharmacological effect of tolvaptan to inhibit water reabsorption can be monitored by measurement of the dynamics of urinary AQP2 levels.
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Abstract
Aquaporins (AQPs) are a 13 member family (AQP0-12) of proteins that act as channels, through which water and, for some family members, glycerol, urea and other small solutes can be transported. Aquaporins are highly abundant in kidney epithelial cells where they play a critical role with respect to water balance. In this review we summarize the current knowledge with respect to the localization and function of AQPs within the kidney tubule, and their role in mammalian water homeostasis and the water balance disorders. Overviews of practical aspects with regard to differential diagnosis for some of these disorders, alongside treatment strategies are also discussed.
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Affiliation(s)
- Hanne B Moeller
- Department of Biomedicine and Center for Interactions of Proteins in Epithelial Transport, Aarhus University, Denmark
| | - Cecilia H Fuglsang
- Department of Biomedicine and Center for Interactions of Proteins in Epithelial Transport, Aarhus University, Denmark
| | - Robert A Fenton
- Department of Biomedicine and Center for Interactions of Proteins in Epithelial Transport, Aarhus University, Denmark.
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Kogiso T, Tokushige K, Hashimoto E, Ikarashi Y, Kodama K, Taniai M, Torii N, Shiratori K. Safety and efficacy of long-term tolvaptan therapy for decompensated liver cirrhosis. Hepatol Res 2016; 46:E194-200. [PMID: 26123753 DOI: 10.1111/hepr.12547] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/14/2015] [Accepted: 06/20/2015] [Indexed: 12/11/2022]
Abstract
AIM Recently, the short-term efficacy of the vasopressin V2 receptor antagonist tolvaptan for the treatment of ascites in cirrhosis was reported. However, the long-term effects remain unknown. Here, we report the clinical features of decompensated cirrhosis treated using long-term tolvaptan therapy, and evaluate its safety and efficacy. METHODS Fifty-five cirrhotic patients hospitalized due to ascites, despite receiving appropriate diuretic treatment, were treated with tolvaptan. We excluded 35 patients due to liver transplant (20.0%), death (28.6%), poor general status (14.3%), improved ascites (5.7%) or other reasons (31.4%). In 20 cases treated with tolvaptan for 6 months, total body water (TBW) and extracellular fluids (ECW) were measured using bioelectric impedance analysis (BIA) with an InBody720. RESULTS The median age of the 20 patients was 64 years (range, 48-90), and 60% were male. The etiology of cirrhosis included hepatitis C (45%), alcohol-induced (20%) and other (35%). The percentage of patients with Child-Pugh class A, B and C was 0%, 40% and 60%, respectively. Biochemical findings revealed that serum creatinine levels and estimated glomerular filtration rate were not affected during 6 months of treatment with tolvaptan, and there was no renal disturbance. The median serum sodium levels were increased from 138 to 139 mEq/L, but serious adverse events related to renal and liver function were not observed. Data also revealed that long-term treatment reduced the BIA-estimated ECW/TBW ratio. CONCLUSION Long-term tolvaptan treatment was a safe and effective treatment for decompensated cirrhosis.
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Affiliation(s)
- Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsutoshi Tokushige
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Etsuko Hashimoto
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Yuichi Ikarashi
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuhisa Kodama
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Makiko Taniai
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Nobuyuki Torii
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Keiko Shiratori
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
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Vukićević T, Schulz M, Faust D, Klussmann E. The Trafficking of the Water Channel Aquaporin-2 in Renal Principal Cells-a Potential Target for Pharmacological Intervention in Cardiovascular Diseases. Front Pharmacol 2016; 7:23. [PMID: 26903868 PMCID: PMC4749865 DOI: 10.3389/fphar.2016.00023] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 01/25/2016] [Indexed: 01/13/2023] Open
Abstract
Arginine-vasopressin (AVP) stimulates the redistribution of water channels, aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane of renal collecting duct principal cells. By this AVP directs 10% of the water reabsorption from the 170 L of primary urine that the human kidneys produce each day. This review discusses molecular mechanisms underlying the AVP-induced redistribution of AQP2; in particular, it provides an overview over the proteins participating in the control of its localization. Defects preventing the insertion of AQP2 into the plasma membrane cause diabetes insipidus. The disease can be acquired or inherited, and is characterized by polyuria and polydipsia. Vice versa, up-regulation of the system causing a predominant localization of AQP2 in the plasma membrane leads to excessive water retention and hyponatremia as in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), late stage heart failure or liver cirrhosis. This article briefly summarizes the currently available pharmacotherapies for the treatment of such water balance disorders, and discusses the value of newly identified mechanisms controlling AQP2 for developing novel pharmacological strategies. Innovative concepts for the therapy of water balance disorders are required as there is a medical need due to the lack of causal treatments.
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Affiliation(s)
- Tanja Vukićević
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association Berlin, Germany
| | - Maike Schulz
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association Berlin, Germany
| | - Dörte Faust
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association Berlin, Germany
| | - Enno Klussmann
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz AssociationBerlin, Germany; German Centre for Cardiovascular ResearchBerlin, Germany
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Fukui H. Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites? World J Gastroenterol 2015; 21:11584-11596. [PMID: 26556988 PMCID: PMC4631962 DOI: 10.3748/wjg.v21.i41.11584] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 08/08/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Hyponatremia is a frequent complication of advanced cirrhosis with ascites associated with increased morbidity and mortality. It is caused by an impairment in the renal capacity to eliminate solute-free water and is considered to be related to persistent secretion of vasopressin despite low serum osmolality. This nonosmotic release of vasopressin is mediated by the autonomic nervous system, which senses the underfilling of arterial vascular component. This reduction of effective arterial blood volume is closely related to the development of ascites. Although the short-time effects of vasopressin V2 receptor antagonists (vaptans) on hyponatremia and ascites have been repeatedly reported, their effects on the long-term management of cirrhotic ascites have not been established yet. Considering that their effects on water diuresis and their safety are limited by severe underfilling state of patients, cautious approaches with adequate monitoring are needed to advanced cirrhosis. Proper indication, adequate doses and new possibility of combination therapy should be explored in the future controlled study. As hyponatremia is frequent obstacle to ascites management, judicious combination with low-dose diuretics may decrease the incidence of refractory ascites. Although vaptans show much promise in the treatment of advanced cirrhosis, the problem of high cost should be solved for the future.
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Geilswijk M, Thomsen KL, Pedersen EB, Vilstrup H, Grønbæk H. Urinary aquaporin-2 excretion before and after transjugular intrahepatic portosystemic shunt insertion for refractory ascites. Scand J Gastroenterol 2015; 50:454-461. [PMID: 25637473 DOI: 10.3109/00365521.2014.962610] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The role of renal aquaporin-2 (AQP2) water channel turnover in patients with liver cirrhosis, portal hypertension and water retention remains unclear. Transjugular intrahepatic portosystemic shunt (TIPS) insertion reduces portal hypertension, improves water excretion and lowers plasma vasopressin. The aim of this study was to establish whether TIPS insertion decreases urinary AQP2 excretion (uAQP2) in parallel with improved water excretion. MATERIAL AND METHODS Fourteen cirrhosis patients with refractory ascites were studied before TIPS insertion and 4 and 12 weeks after insertion. A 24-h urine collection was followed by an oral water load (20 ml/kg body weight) with a 4-h blood and urine sampling. RESULTS TIPS reduced the portal pressure gradient from a median 18(4) (25-75% InterQuartile-range) to 7(2) mmHg, p < 0.05 and the need for diuretics (p < 0.05). TIPS increased plasma sodium from 136(6) mmol/l to 139(4), (p < 0.05) and diuresis from 1650(1043) ml/24 h to 2230(560) (p < 0.05), although the 24-h urinary sodium excretion did not change. There was no change in the baseline uAQP2 before 274(249) ng/(mmol creatinine/24 h) and 12 weeks after TIPS 242(201). There were no systematic changes in uAQP2, plasma vasopressin or other vasoactive substances during the water loads, before or after TIPS. CONCLUSION The effective amelioration of portal hypertension improved the patient's water excretion and plasma sodium, but there was no change in renal AQP2 trafficking or vasopressin. These findings do not support a primary role for renal AQP2 water channels in portal hypertensive water retention.
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Affiliation(s)
- Marianne Geilswijk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , 44 Nørrebrogade, 8000 Aarhus C , Denmark
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Kortenoeven MLA, Fenton RA. Renal aquaporins and water balance disorders. Biochim Biophys Acta Gen Subj 2013; 1840:1533-49. [PMID: 24342488 DOI: 10.1016/j.bbagen.2013.12.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/26/2013] [Accepted: 12/09/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Aquaporins (AQPs) are a family of proteins that can act as water channels. Regulation of AQPs is critical to osmoregulation and the maintenance of body water homeostasis. Eight AQPs are expressed in the kidney of which five have been shown to play a role in body water balance; AQP1, AQP2, AQP3, AQP4 and AQP7. AQP2 in particular is regulated by vasopressin. SCOPE OF REVIEW This review summarizes our current knowledge of the underlying mechanisms of various water balance disorders and their treatment strategies. MAJOR CONCLUSIONS Dysfunctions of AQPs are involved in disorders associated with disturbed water homeostasis. Hyponatremia with increased AQP levels can be caused by diseases with low effective circulating blood volume, such as congestive heart failure, or osmoregulation disorders such as the syndrome of inappropriate secretion of antidiuretic hormone. Treatment consists of fluid restriction, demeclocycline and vasopressin type-2 receptor antagonists. Decreased AQP levels can lead to diabetes insipidus (DI), characterized by polyuria and polydipsia. In central DI, vasopressin production is impaired, while in gestational DI, levels of the vasopressin-degrading enzyme vasopressinase are abnormally increased. Treatment consists of the vasopressin analogue dDAVP. Nephrogenic DI is caused by the inability of the kidney to respond to vasopressin and can be congenital, but is most commonly acquired, usually due to lithium therapy. Treatment consists of sufficient fluid supply, low-solute diet and diuretics. GENERAL SIGNIFICANCE In recent years, our understanding of the underlying mechanisms of water balance disorders has increased enormously, which has opened up several possible new treatment strategies. This article is part of a Special Issue entitled Aquaporins.
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Affiliation(s)
- Marleen L A Kortenoeven
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Interactions of Proteins in Epithelial Transport (InterPrET), Aarhus University, Aarhus, Denmark.
| | - Robert A Fenton
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Interactions of Proteins in Epithelial Transport (InterPrET), Aarhus University, Aarhus, Denmark.
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Habib S, Boyer TD. Vasopressin V2-receptor antagonists in patients with cirrhosis, ascites and hyponatremia. Therap Adv Gastroenterol 2012; 5:189-97. [PMID: 22570679 PMCID: PMC3342571 DOI: 10.1177/1756283x12437357] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Hyponatremia is a common problem in patients with advanced cirrhosis. It develops slowly (paralleling the rate of progression of the liver disease) and usually produces no neurological symptoms, although it may exacerbate hepatic encephalopathy. For patients awaiting liver transplantation a low serum sodium level is a strong predictor of pretransplant mortality, independent of the Model for End-stage Liver Disease score (MELD). The pathogenesis of hyponatremia is related to the hemodynamic changes and secondary neurohormonal adaptations that occur in patients with cirrhosis and ascites. The nonosmotic release of arginine vasopressin is the principle cause of the hyponatremia and vasopressin-receptor antagonists are a new class of drugs recently approved for treatment of cirrhotic hyponatremia. In this article we review the safety and efficacy of V2-receptor antagonists in patients with cirrhosis, ascites and hyponatremia.
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Affiliation(s)
- Shahid Habib
- Department of Medicine, Section of Gastroenterology and Hepatology, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Thomas D. Boyer
- Department of Medicine, Rm 6334, AHSC 245035, 1501 North Campbell Avenue, Tucson, AZ 85724, USA
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Perazzo JC, Tallis S, Delfante A, Souto PA, Lemberg A, Eizayaga FX, Romay S. Hepatic encephalopathy: An approach to its multiple pathophysiological features. World J Hepatol 2012; 4:50-65. [PMID: 22489256 PMCID: PMC3321490 DOI: 10.4254/wjh.v4.i3.50] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Revised: 11/19/2011] [Accepted: 02/24/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.
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Affiliation(s)
- Juan Carlos Perazzo
- Juan Carlos Perazzo, Silvina Tallis, Amalia Delfante, Pablo Andrés Souto, Abraham Lemberg, Francisco Xavier Eizayaga, Salvador Romay, Laboratory of Portal Hypertension and Hepatic Encephalopathy, Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 950, CP 1113, Buenos Aires, Argentina
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Abstract
The development of hyponatremia represents an ominous event in the progression of cirrhosis to end-stage liver disease. It usually develops in those with refractory ascites and is a manifestation of the non-osmotic release of arginine vasopressin (AVP). In the hospitalized cirrhotic patient, hyponatremia is associated with increased disease severity and mortality. In this article, we review the pathophysiology of hyponatremia, its clinical implications, evaluation, and treatment.
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Affiliation(s)
- Elizabeth Ross
- Division of Gastroenterology, Department of Medicine, New York University School of Medicine, New York, New York
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