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Jiang Y, Xue R, Chang Y, Cao D, Liu B, Li Y. The knockout of Gγ subunit HvGS3 by CRISPR/Cas9 gene editing improves the lodging resistance of barley through dwarfing and stem strengthening. TAG. THEORETICAL AND APPLIED GENETICS. THEORETISCHE UND ANGEWANDTE GENETIK 2025; 138:61. [PMID: 40014102 DOI: 10.1007/s00122-025-04853-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/09/2025] [Indexed: 02/28/2025]
Abstract
Gγ subunits participate in multiple biological processes, but their biological function in barley is unknown. Here, CRISPR/Cas9 gene editing was used to knockout HvGS3 in barley. The height of hvgs3 plants were reduced by 37.8 ~ 43.1% compared to wild type, and the culm lodging resistance index (CLRI) of the second internode of stems was increased by 76.6%. The decrease in cell length of the second internode was similar to its node length. The shorter cells may be the main reason for the declines in the internode length and plant height. The number and area of vascular bundles, the epidermal thickness, and the mechanical tissue thickness were significantly higher in hvgs3 due to the higher lignin content. Transcriptome analysis showed higher expression of structural genes related to lignin biosynthesis. Gibberellin (GA) biosynthesis was suppressed through the down-regulation of the GA3ox gene, and the application of gibberellin restored the plant height of hvgs3, indicating that plant height was altered by hindering gibberellin biosynthesis. These results shed new light on the functions of the Gγ subunit GS3 and provide a resource for breeding new lodging-resistant barley cultivars.
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Affiliation(s)
- Yanyan Jiang
- Academy of Agriculture and Forestry Sciences, Qinghai University, Xining, 810016, Qinghai, China
- Key Laboratory of Crop Molecular Breeding, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China
| | - Ruiyin Xue
- Key Laboratory of Crop Molecular Breeding, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China
- Qinghai Normal University, No. 38 Wusi West Road, Xining, Qinghai, China
| | - Yanzi Chang
- Key Laboratory of Crop Molecular Breeding, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dong Cao
- Key Laboratory of Crop Molecular Breeding, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Baolong Liu
- Key Laboratory of Crop Molecular Breeding, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Yun Li
- Key Laboratory of Crop Molecular Breeding, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, Qinghai, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Suzuki T, Ohara M. Role of vasopressin for chronic hypertension in pregnancy. Hypertens Res 2024; 47:2969-2970. [PMID: 39169151 DOI: 10.1038/s41440-024-01855-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024]
Affiliation(s)
- Tomo Suzuki
- Department of Nephrology, Kameda Medical Center, Chiba, Japan.
| | - Mamiko Ohara
- Department of Nephrology, Kameda Medical Center, Chiba, Japan
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Solela G. Prevalence and prognostic role of hypochloremia in patients with acute heart failure in Ethiopia: A single-center retrospective analysis. PLoS One 2024; 19:e0310251. [PMID: 39264907 PMCID: PMC11392231 DOI: 10.1371/journal.pone.0310251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND In patients with heart failure (HF), multiple electrolyte disorders are common, and recent studies have shown that chloride disorders play a significant role in the prognosis of HF. Data about the prevalence and prognostic role of hypochloremia in patients with acute HF (AHF) are scarce in African nations, including Ethiopia. Hence, this study aimed to assess the prevalence, associated factors, and prognostic role of hypochloremia in patients with AHF in Ethiopia. METHODS This was a single-center retrospective analysis of AHF patients, aged ≥15 years, with chloride determination upon admission to the medical wards and medical ICU of Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia, from July 1, 2022, to July 1, 2023. Statistical Package for Social Sciences, version 26, was used to enter and analyze the data. Descriptive analysis was used to summarize clinical profiles, laboratory data, and outcomes of AHF patients stratified by the presence and absence of hypochloremia. Logistic regression analysis was used to determine the factors associated with hypochloremia and to assess the association of hypochloremia and other factors with in-hospital mortality in patients with AHF. A two-tailed P value <0.05 was regarded as statistically significant. RESULTS A total of 267 AHF patients who had chloride determination on admission were included in this study; the mean age was 56.7 years (standard deviation: 18.6), and the gender-based distribution of the patients was nearly equal. The prevalence of hypochloremia was 36.7%. Diastolic blood pressure <60 mm Hg [adjusted odds ratio (AOR) = 3.63, 95% confidence interval (CI), 1.04, 12.72] and hyponatremia (AOR = 29.20, 95% CI, 13.21, 64.56) were significantly associated with hypochloremia. The in-hospital mortality rate was higher in AHF patients with hypochloremia (16.3%) compared to those without hypochloremia (4.7%). The odds of in-hospital mortality among AHF patients with hypochloremia were 2.8 times higher compared to patients without hypochloremia (AOR = 2.82, 95% CI: 1.08, 7.04) after adjusting for ICU admission, systolic blood pressure < 120 mm Hg and diastolic blood pressure < 60 mm Hg. CONCLUSIONS This study revealed a high prevalence of hypochloremia among patients with AHF. Low diastolic blood pressure and hyponatremia were significantly associated with the development of hypochloremia. Most importantly, AHF patients with hypochloremia had a higher in-hospital mortality rate compared to those without hypochloremia. Hence, hypochloremia on admission should be considered a potential prognostic factor in patients with AHF, and further research with a larger sample size is needed to support the findings of this study.
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Affiliation(s)
- Gashaw Solela
- Department of Internal Medicine, Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
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Dhalla NS, Mota KO, Elimban V, Shah AK, de Vasconcelos CML, Bhullar SK. Role of Vasoactive Hormone-Induced Signal Transduction in Cardiac Hypertrophy and Heart Failure. Cells 2024; 13:856. [PMID: 38786079 PMCID: PMC11119949 DOI: 10.3390/cells13100856] [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: 03/25/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably preceded by adaptive or maladaptive cardiac hypertrophy, several biochemical mechanisms have been proposed to explain the development of cardiac hypertrophy and progression to heart failure. One of these includes the activation of different neuroendocrine systems for elevating the circulating levels of different vasoactive hormones such as catecholamines, angiotensin II, vasopressin, serotonin and endothelins. All these hormones are released in the circulation and stimulate different signal transduction systems by acting on their respective receptors on the cell membrane to promote protein synthesis in cardiomyocytes and induce cardiac hypertrophy. The elevated levels of these vasoactive hormones induce hemodynamic overload, increase ventricular wall tension, increase protein synthesis and the occurrence of cardiac remodeling. In addition, there occurs an increase in proinflammatory cytokines and collagen synthesis for the induction of myocardial fibrosis and the transition of adaptive to maladaptive hypertrophy. The prolonged exposure of the hypertrophied heart to these vasoactive hormones has been reported to result in the oxidation of catecholamines and serotonin via monoamine oxidase as well as the activation of NADPH oxidase via angiotensin II and endothelins to promote oxidative stress. The development of oxidative stress produces subcellular defects, Ca2+-handling abnormalities, mitochondrial Ca2+-overload and cardiac dysfunction by activating different proteases and depressing cardiac gene expression, in addition to destabilizing the extracellular matrix upon activating some metalloproteinases. These observations support the view that elevated levels of various vasoactive hormones, by producing hemodynamic overload and activating their respective receptor-mediated signal transduction mechanisms, induce cardiac hypertrophy. Furthermore, the occurrence of oxidative stress due to the prolonged exposure of the hypertrophied heart to these hormones plays a critical role in the progression of heart failure.
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Affiliation(s)
- Naranjan S. Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (V.E.); (S.K.B.)
| | - Karina O. Mota
- Department of Physiology, Center of Biological and Health Sciences, Federal University of Sergipe, Sao Cristóvao 49100-000, Brazil; (K.O.M.); (C.M.L.d.V.)
| | - Vijayan Elimban
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (V.E.); (S.K.B.)
| | - Anureet K. Shah
- Department of Nutrition and Food Science, California State University, Los Angeles, CA 90032-8162, USA;
| | - Carla M. L. de Vasconcelos
- Department of Physiology, Center of Biological and Health Sciences, Federal University of Sergipe, Sao Cristóvao 49100-000, Brazil; (K.O.M.); (C.M.L.d.V.)
| | - Sukhwinder K. Bhullar
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (V.E.); (S.K.B.)
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Perschinka F, Köglberger P, Klein SJ, Joannidis M. [Hyponatremia : Etiology, diagnosis and acute therapy]. Med Klin Intensivmed Notfmed 2023; 118:505-517. [PMID: 37646802 PMCID: PMC10501960 DOI: 10.1007/s00063-023-01049-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 05/09/2023] [Accepted: 05/15/2023] [Indexed: 09/01/2023]
Abstract
Hyponatremia is one of the most common electrolyte disorders in emergency departments and hospitalized patients. Serum sodium concentration is controlled by osmoregulation and volume regulation. Both pathways are regulated via the release of antidiuretic hormone (ADH). Syndrome of inappropriate release of ADH (SIADH) may be caused by neoplasms or pneumonia but may also be triggered by drug use or drug abuse. Excessive fluid intake may also result in a decrease in serum sodium concentration. Rapid alteration in serum sodium concentration leads to cell swelling or cell shrinkage, which primarily causes neurological symptoms. The dynamics of development of hyponatremia and its duration are crucial. In addition to blood testing, a clinical examination and urine analysis are essential in the differential diagnosis of hyponatremia.
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Affiliation(s)
- Fabian Perschinka
- Gemeinsame Einrichtung Internistische Intensiv- und Notfallmedizin, Department für Innere Medizin, Medizinische Universität Innsbruck, Anichstraße 35, 6020, Innsbruck, Österreich
| | - Paul Köglberger
- Gemeinsame Einrichtung Internistische Intensiv- und Notfallmedizin, Department für Innere Medizin, Medizinische Universität Innsbruck, Anichstraße 35, 6020, Innsbruck, Österreich
- Institut für Anästhesiologie und Intensivmedizin, Klinikum Wels, Grieskirchnerstraße 42, 4600, Wels, Österreich
| | - Sebastian J Klein
- Gemeinsame Einrichtung Internistische Intensiv- und Notfallmedizin, Department für Innere Medizin, Medizinische Universität Innsbruck, Anichstraße 35, 6020, Innsbruck, Österreich
| | - Michael Joannidis
- Gemeinsame Einrichtung Internistische Intensiv- und Notfallmedizin, Department für Innere Medizin, Medizinische Universität Innsbruck, Anichstraße 35, 6020, Innsbruck, Österreich.
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Kirkegaard T, Riishede A, Tramm T, Nejsum LN. Aquaglyceroporins in Human Breast Cancer. Cells 2023; 12:2185. [PMID: 37681917 PMCID: PMC10486483 DOI: 10.3390/cells12172185] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 09/09/2023] Open
Abstract
Aquaporins are water channels that facilitate passive water transport across cellular membranes following an osmotic gradient and are essential in the regulation of body water homeostasis. Several aquaporins are overexpressed in breast cancer, and AQP1, AQP3 and AQP5 have been linked to spread to lymph nodes and poor prognosis. The subgroup aquaglyceroporins also facilitate the transport of glycerol and are thus involved in cellular metabolism. Transcriptomic analysis revealed that the three aquaglyceroporins, AQP3, AQP7 and AQP9, but not AQP10, are overexpressed in human breast cancer. It is, however, unknown if they are all expressed in the same cells or have a heterogeneous expression pattern. To investigate this, we employed immunohistochemical analysis of serial sections from human invasive ductal and lobular breast cancers. We found that AQP3, AQP7 and AQP9 are homogeneously expressed in almost all cells in both premalignant in situ lesions and invasive lesions. Thus, potential intervention strategies targeting cellular metabolism via the aquaglyceroporins should consider all three expressed aquaglyceroporins, namely AQP3, AQP7 and AQP9.
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Affiliation(s)
- Teresa Kirkegaard
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark; (T.K.); (A.R.); (T.T.)
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark
| | - Andreas Riishede
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark; (T.K.); (A.R.); (T.T.)
| | - Trine Tramm
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark; (T.K.); (A.R.); (T.T.)
- Department of Pathology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Lene N. Nejsum
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark; (T.K.); (A.R.); (T.T.)
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Abstract
Despite significant advances in management, heart failure continues to impose a significant epidemiologic burden with high prevalence and mortality rates. For decades, sodium has been the serum electrolyte most commonly associated with outcomes; however, challenging the conventional paradigm of sodium's influence, recent studies have identified a more prominent role in serum chloride in the pathophysiology of heart failure. More specifically, hypochloremia is associated with neurohumoral activation, diuretic resistance, and a worse prognosis in patients with heart failure. This review examines basic science, translational research, and clinical studies to better characterize the role of chloride in patients with heart failure and additionally discusses potential new therapies targeting chloride homeostasis that may impact the future of heart failure care.
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Affiliation(s)
- Nayan Arora
- University of Washington, Seattle, Washington
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Ishikawa SE, Funayama H. Hyponatremia Associated with Congestive Heart Failure: Involvement of Vasopressin and Efficacy of Vasopressin Receptor Antagonists. J Clin Med 2023; 12:jcm12041482. [PMID: 36836016 PMCID: PMC9967582 DOI: 10.3390/jcm12041482] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 02/04/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Hyponatremia is frequently found in patients with congestive heart failure. A reduction in effective circulatory blood volume in a volume-expanded patient with decreased cardiac output is linked to a baroreceptor-mediated non-osmotic release of arginine vasopressin (AVP). The increased production of AVP and salt and water retention in the proximal and distal tubules of the kidney by humoral, hemodynamic, and neural mechanisms increase circulatory blood volume and contribute to hyponatremia. Recent studies have indicated that hyponatremia predicts the short-term and long-term prognosis of heart failure by increasing cardiac death and rehospitalization. In addition, the early development of hyponatremia in acute myocardial infarction also predicts the long-term prognosis of worsening heart failure. AVP V2 receptor antagonism may relieve water retention, but it is unknown whether the V2 receptor inhibitor, tolvaptan, improves the long-term prognosis of congestive heart failure. The newly identified natriuretic factor in renal salt wasting has the potential of improving clinical outcomes when combined with a distal diuretic.
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Affiliation(s)
- San-e Ishikawa
- Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan
- Correspondence:
| | - Hiroshi Funayama
- Department of Cardiology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan
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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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Sun Z, Shao X, Wu H, Zhao Y, Cao Y, Li D, Sun Y, Wang Q. Loss of Pten in Renal Tubular Cells Leads to Water Retention by Upregulating AQP2. KIDNEY DISEASES (BASEL, SWITZERLAND) 2022; 9:58-71. [PMID: 36756085 PMCID: PMC9900467 DOI: 10.1159/000528010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 10/26/2022] [Indexed: 12/02/2022]
Abstract
Introduction Phosphatase and tensin (PTEN) is a multifunctional gene associated with the normal development and physiological function of various tissues including the kidney. However, its role in renal tubular reabsorption function has not been well elucidated. Methods We generated a renal tubule-specific Pten knockout mouse model by crossing Ptenfl/fl mice with Ksp-Cre transgenic mice, evaluated the effect of Pten loss on renal tubular function, and investigated the underlying mechanisms. Results Pten loss resulted in abnormal renal structure and function and water retention in multiple organs. Our results also demonstrated that aquaporin-2 (AQP2), an important water channel protein, was upregulated and concentrated on the apical plasma membrane of collecting duct cells, which could be responsible for the impaired water balance in Pten loss mice. The regulation of Pten loss on AQP2 was mediated by protein kinase B (AKT) activation. Conclusions Our results reveal a connection between PTEN gene inactivation and water retention, suggesting the importance of PTEN in normal kidney development and function.
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Affiliation(s)
- Zhuo Sun
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Xiaotong Shao
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Haotian Wu
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Yaxian Zhao
- Department of Pathology, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, China
| | - Yidan Cao
- Department of Pathology, Wuxi No.2 People's Hospital, Wuxi, China
| | - Danhua Li
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China
| | - Ying Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qingling Wang
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, China,*Qingling Wang,
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Shangzu Z, Dingxiong X, ChengJun M, Yan C, Yangyang L, Zhiwei L, Ting Z, Zhiming M, Yiming Z, Liying Z, Yongqi L. Aquaporins: Important players in the cardiovascular pathophysiology. Pharmacol Res 2022; 183:106363. [PMID: 35905892 DOI: 10.1016/j.phrs.2022.106363] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 11/15/2022]
Abstract
Aquaporin is a membrane channel protein widely expressed in body tissues, which can control the input and output of water in cells. AQPs are differentially expressed in different cardiovascular tissues and participate in water transmembrane transport, cell migration, metabolism, inflammatory response, etc. The aberrant expression of AQPs highly correlates with the onset of ischemic heart disease, myocardial ischemia-reperfusion injury, heart failure, etc. Despite much attention to the regulatory role of AQPs in the cardiovascular system, the translation of AQPs into clinical application still faces many challenges, including clarification of the localization of AQPs in the cardiovascular system and mechanisms mediating cardiovascular pathophysiology, as well as the development of cardiovascular-specific AQPs modulators.Therefore, in this study, we comprehensively reviewed the critical roles of AQP family proteins in maintaining cardiovascular homeostasis and described the underlying mechanisms by which AQPs mediated the outcomes of cardiovascular diseases. Meanwhile, AQPs serve as important therapeutic targets, which provide a wide range of opportunities to investigate the mechanisms of cardiovascular diseases and the treatment of those diseases.
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Affiliation(s)
- Zhang Shangzu
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Xie Dingxiong
- Gansu Institute of Cardiovascular Diseases, LanZhou,China
| | - Ma ChengJun
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Chen Yan
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Li Yangyang
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Liu Zhiwei
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Zhou Ting
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Miao Zhiming
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Zhang Yiming
- Gansu University of traditional Chinese Medicine, LanZhou, China
| | - Zhang Liying
- Gansu University of traditional Chinese Medicine, LanZhou, China; Gansu Institute of Cardiovascular Diseases, LanZhou,China.
| | - Liu Yongqi
- Gansu University of traditional Chinese Medicine, LanZhou, China; Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities Gansu University of Chinese Medicine, Lanzhou, China; Key Laboratory of Dunhuang Medicine and Transformation at Provincial and Ministerial Level, Lanzhou, China.
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Kakeshita K, Koike T, Imamura T, Fujioka H, Yamazaki H, Kinugawa K. Altered arginine vasopressin-cyclic AMP-aquaporin 2 pathway in patients with chronic kidney disease. Clin Exp Nephrol 2022; 26:788-796. [PMID: 35503490 DOI: 10.1007/s10157-022-02220-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/28/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND In the collecting ducts of the kidney, arginine vasopressin (AVP), cyclic adenosine monophosphate (cAMP), and aquaporin 2 (AQP2) play a pivotal role in maintaining fluid volume and serum osmolality in humans. However, their association among those with chronic kidney disease (CKD) remains uncertain. METHODS We prospectively included the out-patients with CKD and measured osmolality-related biomarkers including plasma AVP, urine cAMP, urine AQP2, and urine osmolality levels. Association among these parameters at each CKD stage was investigated. RESULTS A total of 121 patients were included (median age 71 years old [61-78], 89 men, estimated glomerular filtration ratio 28.6 [16.4-45.3] mL/min/1.73 m2). Serum osmolality increased as CKD progression, accompanying incremental plasma AVP levels, whereas urine cAMP, urine AQP2, and urine osmolality decreased as CKD progression. At advanced CKD stage, urine cAMP remained low irrespective of the AVP stimulation, whereas urine cAMP levels varied according to the levels of plasma AVP at less advanced CKD stage. The associations between urine cAMP and urine AQP2 and between urine AQP2 and urine osmolality remained preserved irrespective of the CKD stages. CONCLUSIONS Vasopressin type-2 receptor seems to be particularly impaired in patients with advanced CKD, whereas the signal cascade of the downstream of vasopressin type-2 receptor is relatively preserved. Urine cAMP might be a promising marker to estimate the residual function of the collecting duct.
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Affiliation(s)
- Kota Kakeshita
- The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
| | - Tsutomu Koike
- The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
| | - Teruhiko Imamura
- The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
| | - Hayato Fujioka
- The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
| | - Hidenori Yamazaki
- The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
| | - Koichiro Kinugawa
- The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
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Ernstsen CV, Login FH, Schelde AB, Therkildsen J, Møller‐Jensen J, Nørregaard R, Prætorius H, Nejsum LN. Acute pyelonephritis: Increased plasma membrane targeting of renal aquaporin-2. Acta Physiol (Oxf) 2022; 234:e13760. [PMID: 34978750 DOI: 10.1111/apha.13760] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 11/22/2021] [Accepted: 01/01/2022] [Indexed: 12/16/2022]
Abstract
AIM Aquaporin-2 (AQP2) shuttling between intracellular vesicles and the apical plasma membrane is pivotal in arginine vasopressin-mediated urine concentration and is dysregulated in multiple diseases associated with water balance disorders. Children and adults with acute pyelonephritis have a urinary concentration defect and studies in children revealed increased AQP2 excretion in the urine. This study aimed to analyse AQP2 trafficking in response to acute pyelonephritis. METHODS Immunofluorescence analysis was used to evaluate subcellular localization of AQP2 and AQP2-S256A (mimicking non-phosphorylated AQP2 on serine 256) in cells stimulated with bacterial lysates and of AQP2 and pS256-AQP2 in a mouse model at day 5 of acute pyelonephritis. Western blotting was used to evaluate AQP2 levels and AQP2 phosphorylation on S256 upon incubation with bacterial lysates. Time-lapse imaging was used to measure intracellular cAMP levels in response to incubation with bacterial lysates. RESULTS In cell cultures, lysates from both uropathogenic and nonpathogenic bacteria-mediated AQP2 plasma membrane targeting and increased AQP2 phosphorylation on serine 256 (pS256) without increasing cAMP levels. Both bacterial lysates induced plasma membrane targeting of AQP2-S256A. Immunofluorescence analysis of renal sections from mice after 5 days of acute pyelonephritis revealed apical plasma membrane targeting of AQP2 and pS256-AQP2 in inner medullary collecting ducts. CONCLUSION Uropathogenic bacteria induce AQP2 plasma membrane targeting in vitro and in vivo. cAMP levels were not elevated by the bacterial lysates and AQP2 plasma membrane targeting could occur without S256 phosphorylation. This may explain increased AQP2 excretion in the urine during acute pyelonephritis.
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Affiliation(s)
- Christina V. Ernstsen
- Department of Clinical Medicine Aarhus University Aarhus Denmark
- Department of Molecular Biology and Genetics Aarhus University Aarhus Denmark
| | | | | | | | - Jakob Møller‐Jensen
- Department of Biochemistry and Molecular Biology University of Southern Denmark Odense Denmark
| | - Rikke Nørregaard
- Department of Clinical Medicine Aarhus University Aarhus Denmark
| | | | - Lene N. Nejsum
- Department of Clinical Medicine Aarhus University Aarhus Denmark
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14
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Dutta A, Das M. Deciphering the Role of Aquaporins in Metabolic Diseases: A Mini Review. Am J Med Sci 2022; 364:148-162. [DOI: 10.1016/j.amjms.2021.10.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 06/16/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022]
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15
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Bruun-Sørensen AS, Edamana S, Login FH, Borgquist S, Nejsum LN. Aquaporins in pancreatic ductal adenocarcinoma. APMIS 2021; 129:700-705. [PMID: 34582595 DOI: 10.1111/apm.13184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/24/2021] [Indexed: 12/18/2022]
Abstract
Aquaporins are water channel proteins facilitating passive transport of water across cellular membranes. Aquaporins are over- or ectopically expressed in a multitude of cancers, including pancreatic ductal adenocarcinoma, which is a highly aggressive cancer with low survival rate. Evidence suggests that aquaporins can affect multiple cellular processes involved in cancer development and progression including epithelial-mesenchymal transition, cellular migration, cell proliferation, invasion, and cellular adhesions. In pancreatic ductal adenocarcinoma, aquaporin-1, aquaporin-3, and aquaporin-5 are overexpressed and have been associated with metastatic processes and poor survival. Thus, aquaporin expression has been suggested as diagnostic markers and therapeutic targets in pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Anne Sofie Bruun-Sørensen
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
| | - Sarannya Edamana
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Frédéric H Login
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Signe Borgquist
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
- Department of Oncology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden
| | - Lene N Nejsum
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
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16
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Ranieri M, Di Mise A, Centrone M, D'Agostino M, Tingskov SJ, Venneri M, Pellegrino T, Difonzo G, Caponio F, Norregaard R, Valenti G, Tamma G. Olive Leaf Extract (OLE) impaired vasopressin-induced aquaporin-2 trafficking through the activation of the calcium-sensing receptor. Sci Rep 2021; 11:4537. [PMID: 33633156 PMCID: PMC7907100 DOI: 10.1038/s41598-021-83850-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Vasopressin (AVP) increases water permeability in the renal collecting duct through the regulation of aquaporin-2 (AQP2) trafficking. Several disorders, including hypertension and inappropriate antidiuretic hormone secretion (SIADH), are associated with abnormalities in water homeostasis. It has been shown that certain phytocompounds are beneficial to human health. Here, the effects of the Olive Leaf Extract (OLE) have been evaluated using in vitro and in vivo models. Confocal studies showed that OLE prevents the vasopressin induced AQP2 translocation to the plasma membrane in MCD4 cells and rat kidneys. Incubation with OLE decreases the AVP-dependent increase of the osmotic water permeability coefficient (Pf). To elucidate the possible effectors of OLE, intracellular calcium was evaluated. OLE increases the intracellular calcium through the activation of the Calcium Sensing Receptor (CaSR). NPS2143, a selective CaSR inhibitor, abolished the inhibitory effect of OLE on AVP-dependent water permeability. In vivo experiments revealed that treatment with OLE increases the expression of the CaSR mRNA and decreases AQP2 mRNA paralleled by an increase of the AQP2-targeting miRNA-137. Together, these findings suggest that OLE antagonizes vasopressin action through stimulation of the CaSR indicating that this extract may be beneficial to attenuate disorders characterized by abnormal CaSR signaling and affecting renal water reabsorption.
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Affiliation(s)
- Marianna Ranieri
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy.
| | - Annarita Di Mise
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy
| | - Mariangela Centrone
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy
| | - Mariagrazia D'Agostino
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy
| | | | - Maria Venneri
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy
| | - Tommaso Pellegrino
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy
| | - Graziana Difonzo
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Caponio
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Rikke Norregaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Giovanna Valenti
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy
| | - Grazia Tamma
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, 70125, Bari, Italy.
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17
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Sparapani S, Millet-Boureima C, Oliver J, Mu K, Hadavi P, Kalostian T, Ali N, Avelar CM, Bardies M, Barrow B, Benedikt M, Biancardi G, Bindra R, Bui L, Chihab Z, Cossitt A, Costa J, Daigneault T, Dault J, Davidson I, Dias J, Dufour E, El-Khoury S, Farhangdoost N, Forget A, Fox A, Gebrael M, Gentile MC, Geraci O, Gnanapragasam A, Gomah E, Haber E, Hamel C, Iyanker T, Kalantzis C, Kamali S, Kassardjian E, Kontos HK, Le TBU, LoScerbo D, Low YF, Mac Rae D, Maurer F, Mazhar S, Nguyen A, Nguyen-Duong K, Osborne-Laroche C, Park HW, Parolin E, Paul-Cole K, Peer LS, Philippon M, Plaisir CA, Porras Marroquin J, Prasad S, Ramsarun R, Razzaq S, Rhainds S, Robin D, Scartozzi R, Singh D, Fard SS, Soroko M, Soroori Motlagh N, Stern K, Toro L, Toure MW, Tran-Huynh S, Trépanier-Chicoine S, Waddingham C, Weekes AJ, Wisniewski A, Gamberi C. The Biology of Vasopressin. Biomedicines 2021; 9:89. [PMID: 33477721 PMCID: PMC7832310 DOI: 10.3390/biomedicines9010089] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/29/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Chiara Gamberi
- Biology Department, Concordia University, Montreal, QC H4B 1R6, Canada; (S.S.); (C.M.-B.); (J.O.); (K.M.); (P.H.); (T.K.); (N.A.); (C.M.A.); (M.B.); (B.B.); (M.B.); (G.B.); (R.B.); (L.B.); (Z.C.); (A.C.); (J.C.); (T.D.); (J.D.); (I.D.); (J.D.); (E.D.); (S.E.-K.); (N.F.); (A.F.); (A.F.); (M.G.); (M.C.G.); (O.G.); (A.G.); (E.G.); (E.H.); (C.H.); (T.I.); (C.K.); (S.K.); (E.K.); (H.K.K.); (T.B.U.L.); (D.L.); (Y.F.L.); (D.M.R.); (F.M.); (S.M.); (A.N.); (K.N.-D.); (C.O.-L.); (H.W.P.); (E.P.); (K.P.-C.); (L.S.P.); (M.P.); (C.-A.P.); (J.P.M.); (S.P.); (R.R.); (S.R.); (S.R.); (D.R.); (R.S.); (D.S.); (S.S.F.); (M.S.); (N.S.M.); (K.S.); (L.T.); (M.W.T.); (S.T.-H.); (S.T.-C.); (C.W.); (A.J.W.); (A.W.)
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18
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Zhu X, Huang Y, Li S, Ge N, Li T, Wang Y, Liu K, Liu C. Glucocorticoids Reverse Diluted Hyponatremia Through Inhibiting Arginine Vasopressin Pathway in Heart Failure Rats. J Am Heart Assoc 2020; 9:e014950. [PMID: 32390535 PMCID: PMC7660850 DOI: 10.1161/jaha.119.014950] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background Arginine vasopressin dependent antidiuresis plays a key role in water‐sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure‐volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure‐volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal‐collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide‐sensitive Na‐K‐2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.
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Affiliation(s)
- Xiaoran Zhu
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China.,Department of Pharmacy Hebei General Hospital Shijiazhuang China
| | - Yaomeng Huang
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China
| | - Shuyu Li
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China.,Department of Cardiovascular Medicine Fengnan District Hospital Tangshan China
| | - Ning Ge
- Regenerative Medicine Institute School of Medicine National University of Ireland Galway Ireland
| | - Tongxin Li
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China
| | - Yu Wang
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China
| | - Kunshen Liu
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China
| | - Chao Liu
- The First Cardiology Division The First Hospital of Hebei Medical University Shijiazhuang China
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19
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Abstract
Aquaporin (AQP) water channels are important in the function of the kidney. Constitutively expressed AQP1 in the proximal tubule and descending limb is important in normal fluid absorption and in the counter-current multiplication system. The vasopressin-regulated shuttling of AQP2 is essential in antidiuresis and the regulation of water balance. Genetic damage to AQPs, or pathological changes in expression or function, impair renal water handling. The most striking examples of this involve disruption of AQP2 function, which can result in profound nephrogenic diabetes insipidus. Aquaporin 1 is present in capillaries and venules and appears to be important in peritoneal dialysis, where it appears to represent the “ultrasmall pores” of the three-pore model. Decreased expression or function of AQP1 may be responsible for some cases of ultrafiltration failure, but further evidence will be required to establish whether this is the case.
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Affiliation(s)
- David Marples
- School of Biomedical Science, University of Leeds, United Kingdom
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20
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21
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Perioperative urinary excretion of aquaporin-2 dependent upon vasopressin in cardiac surgery. Heart Vessels 2019; 35:712-718. [DOI: 10.1007/s00380-019-01533-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/01/2019] [Indexed: 10/25/2022]
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22
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Zheng H, Liu X, Katsurada K, Patel KP. Renal denervation improves sodium excretion in rats with chronic heart failure: effects on expression of renal ENaC and AQP2. Am J Physiol Heart Circ Physiol 2019; 317:H958-H968. [PMID: 31490733 DOI: 10.1152/ajpheart.00299.2019] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changed the expressions of renal sodium transporters ENaC, sodium-hydrogen exchanger-3 proteins (NHE3), and water channel aquaporin 2 (AQP2) in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, surgical bilateral RDN was performed. The expression of ENaC, NHE3, and AQP2 in both renal cortex and medulla were measured. As a functional test for ENaC activation, diuretic and natriuretic responses to ENaC inhibitor benzamil were monitored in four groups of rats (Sham, Sham+RDN, CHF, CHF+RDN). Western blot analysis indicated that RDN (1 wk later) significantly reduced protein levels of α-ENaC, β-ENaC, γ-ENaC, and AQP2 in the renal cortex of CHF rats. RDN had no significant effects on the protein expression of kidney NHE3 in both Sham and CHF rats. Immunofluorescence studies of kidney sections confirmed the reduced signaling of ENaC and AQP2 in the CHF+RDN rats compared with the CHF rats. There were increases in diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. RDN reduced the diuretic and natriuretic responses to benzamil in CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of ENaC and AQP2 and subsequent pathophysiology of renal sodium and water retention associated with CHF.NEW & NOTEWORTHY This is the first study to show in a comprehensive way that renal denervation initiated after a period of chronic heart failure reduces the expression of epithelial sodium channels and aquaporin 2 leading to reduced epithelial sodium channel function and sodium retention.
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Affiliation(s)
- Hong Zheng
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota
| | - Xuefei Liu
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota
| | - Kenichi Katsurada
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Kaushik P Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
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23
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Holst MR, Nejsum LN. A versatile aquaporin-2 cell system for quantitative temporal expression and live cell imaging. Am J Physiol Renal Physiol 2019; 317:F124-F132. [PMID: 31091121 DOI: 10.1152/ajprenal.00150.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aquaporin-2 (AQP2) fine tunes urine concentration in response to the antidiuretic hormone vasopressin. In addition, AQP2 has been suggested to promote cell migration and epithelial morphogenesis. A cell system allowing temporal and quantitative control of expression levels of AQP2 and phospho-mimicking mutants has been missing, as has a system allowing expression of fluorescently tagged AQP2 for time-lapse imaging. In the present study, we generated and validated a Flp-In T-REx Madin-Darby canine kidney cell system for temporal and quantitative control of AQP2 and phospho-mimicking mutants. We verified that expression levels can be temporally and quantitatively controlled and that AQP2 translocated to the plasma membrane in response to elevated cAMP, which also induced S256 phosphorylation. The phospho-mimicking mutants AQP2-S256A and AQP2-S256D localized as previously described, primarily intracellular and to the plasma membrane, respectively. Induction of AQP2 expression in combination with transient, low expression of enhanced green fluorescent protein-tagged AQP2 enabled expression without aggregation and correct translocation in response to elevated cAMP. Interestingly, time-lapse imaging revealed AQP2-containing tubulating endosomes and that tubulation significantly decreased 30 min after cAMP elevation. This was mirrored by the phospho-mimicking mutants AQP2-S256A and AQP2-S256D, where AQP2-S256A-containing endosomes tubulated, whereas AQP2-S256D-containing endosomes did not. Thus, this cell system enables a multitude of cell-based assays warranted to provide deeper insights into the mechanisms of AQP2 regulation and effects on cell migration and epithelial morphogenesis.
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Affiliation(s)
- Mikkel R Holst
- Department of Clinical Medicine, Aarhus University , Aarhus , Denmark
| | - Lene N Nejsum
- Department of Clinical Medicine, Aarhus University , Aarhus , Denmark
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24
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Verkerk AO, Lodder EM, Wilders R. Aquaporin Channels in the Heart-Physiology and Pathophysiology. Int J Mol Sci 2019; 20:ijms20082039. [PMID: 31027200 PMCID: PMC6514906 DOI: 10.3390/ijms20082039] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/19/2019] [Accepted: 04/23/2019] [Indexed: 12/11/2022] Open
Abstract
Mammalian aquaporins (AQPs) are transmembrane channels expressed in a large variety of cells and tissues throughout the body. They are known as water channels, but they also facilitate the transport of small solutes, gasses, and monovalent cations. To date, 13 different AQPs, encoded by the genes AQP0–AQP12, have been identified in mammals, which regulate various important biological functions in kidney, brain, lung, digestive system, eye, and skin. Consequently, dysfunction of AQPs is involved in a wide variety of disorders. AQPs are also present in the heart, even with a specific distribution pattern in cardiomyocytes, but whether their presence is essential for proper (electro)physiological cardiac function has not intensively been studied. This review summarizes recent findings and highlights the involvement of AQPs in normal and pathological cardiac function. We conclude that AQPs are at least implicated in proper cardiac water homeostasis and energy balance as well as heart failure and arsenic cardiotoxicity. However, this review also demonstrates that many effects of cardiac AQPs, especially on excitation-contraction coupling processes, are virtually unexplored.
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Affiliation(s)
- Arie O Verkerk
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
- Department of Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Elisabeth M Lodder
- Department of Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Ronald Wilders
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
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25
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Wang A, Hirose T, Ohsaki Y, Takahashi C, Sato E, Oba-Yabana I, Kinugasa S, Muroya Y, Ito S, Mori T. Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats. Clin Exp Nephrol 2018; 23:455-464. [PMID: 30426292 DOI: 10.1007/s10157-018-1669-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/29/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. METHODS Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. RESULTS Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. CONCLUSION HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.
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Affiliation(s)
- Anyi Wang
- Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Takuo Hirose
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Yusuke Ohsaki
- Division of Integrated Renal Replacement Therapy, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Chika Takahashi
- Division of Integrated Renal Replacement Therapy, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Emiko Sato
- Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Ikuko Oba-Yabana
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Satoshi Kinugasa
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Yoshikazu Muroya
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Sadayoshi Ito
- Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Takefumi Mori
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan. .,Division of Integrated Renal Replacement Therapy, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo, Aoba, Sendai, 980-8574, Japan.
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Abstract
INTRODUCTION Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. Furthermore, it is associated with increased morbidity and mortality. AREAS COVERED This review discusses the efficacy and side effects of the currently available treatment options for hyponatremia and the differences in the pharmacological approach between the European and USA guidelines. Additionally, the authors provide their expert perspectives on current treatment strategies and what they expect from this field in the future. EXPERT OPINION Several pharmacological options are available for the treatment of hyponatremia, but data from trials examining and comparing these treatments are missing. Regarding chronic hyponatremia, the role of vaptans should be further analyzed, focusing on comparisons with other active treatments on patient-relevant outcomes and not only on serum sodium concentration. Clinicians should be cautious to an overly rapid increase in serum sodium levels with all available treatment strategies. Finally, it is important to ascertain whether correction of serum sodium levels improves mortality in hyponatremic patients.
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Affiliation(s)
- Theodosios Filippatos
- a Department of Internal Medicine, School of Medicine , University of Crete , Crete , Greece
| | - Moses Elisaf
- b Department of Internal Medicine, School of Medicine , University of Ioannina , Ioannina , Greece
| | - George Liamis
- b Department of Internal Medicine, School of Medicine , University of Ioannina , Ioannina , Greece
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Tominaga N, Kida K, Inomata T, Sato N, Izumi T, Akashi YJ, Shibagaki Y. Effects of Tolvaptan Addition to Furosemide in Normo- and Hyponatremia Patients with Heart Failure and Chronic Kidney Disease Stages G3b-5: A Subanalysis of the K-STAR Study. Am J Nephrol 2017; 46:417-426. [PMID: 29130954 DOI: 10.1159/000481995] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/04/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND Tolvaptan increases free water clearance (aquaresis) and thereby improves hyponatremia. Although hyponatremia on admission is common in patients with congestive heart failure (CHF), little is known regarding the response to tolvaptan in those who also have chronic kidney disease (CKD) with or without hyponatremia. The aim of this subanalysis was to investigate the differences in treatment response between normo- and hyponatremia patients with CHF and CKD stages G3b-5. METHODS The Kanagawa Aquaresis Investigators Trial of Tolvaptan on HF Patients with Renal Impairment (K-STAR) was a multicenter, open-label, randomized, controlled prospective clinical trial that included 81 Japanese patients with CHF and residual signs of congestion despite oral furosemide treatment (≥40 mg/day). All patients were randomly assigned to 7-day treatment with either ≤15 mg/day of new add-on tolvaptan or ≤40 mg/day of increased furosemide. A subanalysis was conducted for 73 patients, who were classified into 2 groups according to their assigned treatment, then further stratified into 2 subgroups according to their serum sodium concentration [Na+]. The differences between the urine and serum parameters from day 1 to 3 were compared between the groups and between the subgroups in each group. RESULTS The change (Δ) in urine volume (ΔUV) and Δurine osmolality were greater in the tolvaptan group than in the furosemide group; however, ΔUV and Δurine osmolality did not show significant differences between the normonatremia subgroup and the hyponatremia subgroup in each group. In addition, Δserum [Na+] was greater in the tolvaptan group, although the change was not clinically significant. In contrast, Δserum [Na+] did not show significant differences between the normo- and hyponatremia subgroups in each group. CONCLUSION Tolvaptan added to furosemide resulted in a greater diuretic effect than increased furosemide, even in normonatremia patients with CHF complicated by CKD stages G3b-5 in the very early treatment phase.
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Affiliation(s)
- Naoto Tominaga
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Keisuke Kida
- Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Takayuki Inomata
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Naoki Sato
- Division of Cardiology, Department of Internal Medicine, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan
| | - Tohru Izumi
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Kanagawa, Japan
- Division of Cardiology, Department of Internal Medicine, Niigata Minami Hospital, Niigata, Japan
| | - Yoshihiro J Akashi
- Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Yugo Shibagaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
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Ishikawa SE. Is Exaggerated Release of Arginine Vasopressin an Endocrine Disorder? Pathophysiology and Treatment. J Clin Med 2017; 6:jcm6110102. [PMID: 29088071 PMCID: PMC5704119 DOI: 10.3390/jcm6110102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 10/27/2017] [Accepted: 10/30/2017] [Indexed: 12/05/2022] Open
Abstract
Exaggerated release of arginine vasopressin (AVP) is profoundly involved in impaired water excretion and related hyponatremia. Such disorders underlie syndromes of inappropriate secretion of antidiuretic hormone (SIADH) and edematous diseases, such as congestive heart failure and decompensated liver cirrhosis. All the causes are fundamentally from non-endocrine diseases. AVP-induced water retention could produce hyponatremia, and further accelerate poor long-term outcome of edematous diseases. Administration of AVP V2 receptor antagonists verifies how much AVP is involved in the pathogenesis of the impaired water excretion. The present paper demonstrated that exaggerated release of AVP plays a crucial role as an accessory endocrine disorder in pathological states of water retention and dilutional hyponatremia in non-endocrine disorders.
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Affiliation(s)
- San-E Ishikawa
- Department of Endocrinology and Metabolism, International University of Health and Welfare Hospital, Nasushiobara 329-2763, Tochigi, Japan.
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Li Y, Wang W, Jiang T, Yang B. Aquaporins in Urinary System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 969:131-148. [PMID: 28258571 DOI: 10.1007/978-94-024-1057-0_9] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Several aquaporin (AQP )-type water channels are expressed in kidney: AQP1 in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2 -6 in the collecting duct; AQP7 in the proximal tubule; AQP8 in the proximal tubule and collecting duct; and AQP11 in the endoplasmic reticulum of proximal tubule cells. AQP2 is the vasopressin-regulated water channel that is important in hereditary and acquired diseases affecting urine-concentrating ability. The roles of AQPs in renal physiology and transepithelial water transport have been determined using AQP knockout mouse models. This chapter describes renal physiologic insights revealed by phenotypic analysis of AQP knockout mice and the prospects for further basic and clinical studies.
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Affiliation(s)
- Yingjie Li
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Weiling Wang
- State Key Laboratory of Natural and Biomimetic Drugs, and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Tao Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Baoxue Yang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
- Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, 100191, China.
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Tie L, Wang D, Shi Y, Li X. Aquaporins in Cardiovascular System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 969:105-113. [PMID: 28258568 DOI: 10.1007/978-94-024-1057-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent studies have shown that some aquaporins (AQPs ), including AQP1, AQP4, AQP7 and AQP9, are expressed in endothelial cells, vascular smooth muscle cells and heart of cardiovascular system. These AQPs are involved in the cardiovascular function and in pathological process of related diseases, such as cerebral ischemia , congestion heart failure , hypertension and angiogenesis. Therefore, it is important to understand the accurate association between AQPs and cardiovascular system, which may provide novel approaches to prevent and treat related diseases. Here we will discuss the expression and physiological function of AQPs in cardiovascular system and summarize recent researches on AQPs related cardiovascular diseases.
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Affiliation(s)
- Lu Tie
- State Key Laboratory of Natural and Biomimetic Drugs, and Department of Pharmacology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing, 100191, China
| | - Di Wang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Yundi Shi
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Xuejun Li
- State Key Laboratory of Natural and Biomimetic Drugs, and Department of Pharmacology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing, 100191, China.
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Villar IC, Bubb KJ, Moyes AJ, Steiness E, Gulbrandsen T, Levy FO, Hobbs AJ. Functional pharmacological characterization of SER100 in cardiovascular health and disease. Br J Pharmacol 2016; 173:3386-3401. [PMID: 27667485 DOI: 10.1111/bph.13634] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 09/07/2016] [Accepted: 09/15/2016] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND AND PURPOSE SER100 is a selective nociceptin (NOP) receptor agonist with sodium-potassium-sparing aquaretic and anti-natriuretic activity. This study was designed to characterize the functional cardiovascular pharmacology of SER100 in vitro and in vivo, including experimental models of cardiovascular disease. EXPERIMENTAL APPROACH Haemodynamic, ECG parameters and heart rate variability (HRV) were determined using radiotelemetry in healthy, conscious mice. The haemodynamic and vascular effects of SER100 were also evaluated in two models of cardiovascular disease, spontaneously hypertensive rats (SHR) and murine hypoxia-induced pulmonary hypertension (PH). To elucidate mechanisms underlying the pharmacology of SER100, acute blood pressure recordings were performed in anaesthetized mice, and the reactivity of rodent aorta and mesenteric arteries in response to electrical- and agonist-stimulation assessed. KEY RESULTS SER100 caused NOP receptor-dependent reductions in mean arterial blood pressure and heart rate that were independent of NO. The hypotensive and vasorelaxant actions of SER100 were potentiated in SHR compared with Wistar Kyoto. Moreover, SER100 reduced several indices of disease severity in experimental PH. Analysis of HRV indicated that SER100 decreased the low/high frequency ratio, an indicator of sympatho-vagal balance, and in electrically stimulated mouse mesenteric arteries SER100 inhibited sympathetic-induced contractions. CONCLUSIONS AND IMPLICATIONS SER100 exerts a chronic hypotensive and bradycardic effects in rodents, including models of systemic and pulmonary hypertension. SER100 produces its cardiovascular effects, at least in part, by inhibition of cardiac and vascular sympathetic activity. SER100 may represent a novel therapeutic candidate in systemic and pulmonary hypertension.
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Affiliation(s)
- Inmaculada C Villar
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kristen J Bubb
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Amie J Moyes
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | | | | | - Finn Olav Levy
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Arnspang EC, Login FH, Koffman JS, Sengupta P, Nejsum LN. AQP2 Plasma Membrane Diffusion Is Altered by the Degree of AQP2-S256 Phosphorylation. Int J Mol Sci 2016; 17:ijms17111804. [PMID: 27801846 PMCID: PMC5133805 DOI: 10.3390/ijms17111804] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 09/15/2016] [Accepted: 09/22/2016] [Indexed: 01/21/2023] Open
Abstract
Fine tuning of urine concentration occurs in the renal collecting duct in response to circulating levels of arginine vasopressin (AVP). AVP stimulates intracellular cAMP production, which mediates exocytosis of sub-apical vesicles containing the water channel aquaporin-2 (AQP2). Protein Kinase A (PKA) phosphorylates AQP2 on serine-256 (S256), which triggers plasma membrane accumulation of AQP2. This mediates insertion of AQP2 into the apical plasma membrane, increasing water permeability of the collecting duct. AQP2 is a homo-tetramer. When S256 on all four monomers is changed to the phosphomimic aspartic acid (S256D), AQP2-S256D localizes to the plasma membrane and internalization is decreased. In contrast, when S256 is mutated to alanine (S256A) to mimic non-phosphorylated AQP2, AQP2-S256A localizes to intracellular vesicles as well as the plasma membrane, with increased internalization from the plasma membrane. S256 phosphorylation is not necessary for exocytosis and dephosphorylation is not necessary for endocytosis, however, the degree of S256 phosphorylation is hypothesized to regulate the kinetics of AQP2 endocytosis and thus, retention time in the plasma membrane. Using k-space Image Correlation Spectroscopy (kICS), we determined how the number of phosphorylated to non-phosphorylated S256 monomers in the AQP2 tetramer affects diffusion speed of AQP2 in the plasma membrane. When all four monomers mimicked constitutive phosphorylation (AQP2-S256D), diffusion was faster than when all four were non-phosphorylated (AQP2-S256A). AQP2-WT diffused at a speed similar to that of AQP2-S256D. When an average of two or three monomers in the tetramer were constitutively phosphorylated, the average diffusion coefficients were not significantly different to that of AQP2-S256D. However, when only one monomer was phosphorylated, diffusion was slower and similar to AQP2-S256A. Thus, AQP2 with two to four phosphorylated monomers has faster plasma membrane kinetics, than the tetramer which contains just one or no phosphorylated monomers. This difference in diffusion rate may reflect behavior of AQP2 tetramers destined for either plasma membrane retention or endocytosis.
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Affiliation(s)
- Eva C Arnspang
- Department of Clinical Medicine, Aarhus University, DK-8000 Aarhus C, Denmark.
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Frédéric H Login
- Department of Clinical Medicine, Aarhus University, DK-8000 Aarhus C, Denmark.
| | - Jennifer S Koffman
- Department of Interdisciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark.
| | - Prabuddha Sengupta
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Lene N Nejsum
- Department of Clinical Medicine, Aarhus University, DK-8000 Aarhus C, Denmark.
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Abstract
Disorders of sodium and water metabolism are frequently encountered in hospitalized patients. Hyponatremia in critically ill patients can cause significant morbidity and mortality. Inappropriate treatment of hyponatremia can add to the problem. The diagnosis and management of salt and water abnormalities in critically ill patients is often challenging. The increasing knowledge about aquaporins and the role of vasopressin in water metabolism has enhanced our understanding of these disorders. The authors have outlined the general approach to the diagnosis and management of hyponatremia. A systematic approach by clinicians, using a detailed history, physical examination, and relevant diagnostic tests, will assist in efficient management of salt and water problems.
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Affiliation(s)
- T J Vachharajani
- Louisiana State University Health Sciences Center and Overton Brooks Veterans Affairs Medical Center, Shreveport, LA 71130, USA
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34
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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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Abstract
Heart failure (HF) is one of the most common causes of hospitalization and mortality in the modern Western world and an increasing proportion of the population will be affected by HF in the future. Although HF management has improved quality of life and prognosis, mortality remains very high despite therapeutic options. Medical management consists of a neurohormonal blockade of an overly activated neurohormonal axis. No single marker has been able to predict or monitor HF with respect to disease progression, hospitalization, or mortality. New methods for diagnosis, monitoring therapy, and prognosis are warranted. Copeptin, a precursor of pre-provasopressin, is a new biomarker in HF with promising potential. Copeptin has been found to be elevated in both acute and chronic HF and is associated with prognosis. Copeptin, in combination with other biomarkers, could be a useful marker in the monitoring of disease severity and as a predictor of prognosis and survival in HF.
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Affiliation(s)
- Louise Balling
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
| | - Finn Gustafsson
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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Zheng H, Liu X, Sharma NM, Li Y, Pliquett RU, Patel KP. Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure. Hypertension 2015; 67:197-205. [PMID: 26628676 DOI: 10.1161/hypertensionaha.115.05838] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 10/30/2015] [Indexed: 12/31/2022]
Abstract
One of the key mechanisms involved in renal Na(+) retention in chronic heart failure (CHF) is activation of epithelial Na(+) channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC, resulting in renal Na(+) retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared with sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06, and plasmin 3.57 versus sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch clamp was conducted in cultured renal collecting duct M-1 cells to record Na(+) currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na(+) inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ≈2-folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid, which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na(+) retention commonly observed in CHF.
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Affiliation(s)
- Hong Zheng
- From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.)
| | - Xuefei Liu
- From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.)
| | - Neeru M Sharma
- From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.)
| | - Yulong Li
- From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.)
| | - Rainer U Pliquett
- From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.)
| | - Kaushik P Patel
- From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.).
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Wang Y, Bu J, Zhang Q, Chen K, Zhang J, Bao X. Expression pattern of aquaporins in patients with primary nephrotic syndrome with edema. Mol Med Rep 2015; 12:5625-32. [PMID: 26261083 PMCID: PMC4581814 DOI: 10.3892/mmr.2015.4209] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 04/20/2015] [Indexed: 01/10/2023] Open
Abstract
The association between the expression of aquaporins (AQPs) in kidney tissues and the occurrence of edema in nephrotic syndrome (NS) remains unclear. The current study aimed to investigate this association. A total of 54 patients with primary glomerular disease, diagnosed by renal biopsy, were divided into three groups: Control, NS without edema and NS with edema. The expression of AQP1, AQP2, AQP3 and AQP4 in kidney tissues from these patients was assessed using immunohistochemistry, and urinary AQP concentrations were quantified by ELISA. Comparison of the three groups was conducted using one way analysis of variance, independent samples t-test or the Chi-square test. AQP1 was strongly expressed in the proximal tubules. The proportion of the AQP1-positive area in kidney tissues from patients with NS with edema was significantly reduced, in comparison with the other two groups. By contrast, the proportion of the AQP2-positive area in the NS with edema group was significantly higher than that of the other two groups; significant differences were also observed between the control and NS without edema groups for this parameter. Urinary AQP2 concentrations in patients with NS (with and without edema) were significantly higher than that of the control group, and exhibited a significant positive correlation with kidney tissue AQP2 concentrations. The present study demonstrated the abnormal expression pattern of AQP1-AQP4 in the kidney tissues of patients with NS, providing a basis for an improved understanding of the role of AQP in the pathogenesis of NS.
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Affiliation(s)
- Yu Wang
- Department of Nephrology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
| | - Jimei Bu
- Department of Nephrology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
| | - Qing Zhang
- Department of Nephrology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
| | - Kai Chen
- Department of Nephrology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
| | - Jihong Zhang
- Department of Nephrology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
| | - Xiaorong Bao
- Department of Nephrology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
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Zeng QC, Wu ZL, Huang YL, Hua JH, Ye TC, Lai WY, Ren H, Xu DL. Effects of Qili Qiangxin capsule on renal aquaporin-2 expression in rats with chronic heart failure. Eur Heart J Suppl 2015; 17:C42-C48. [DOI: 10.1093/eurheartj/suv030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
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Lin QQ, Lin R, Ji QL, Zhang JY, Wang WR, Yang LN, Zhang KF. Effect of exercise training on renal function and renal aquaporin-2 expression in rats with chronic heart failure. Clin Exp Pharmacol Physiol 2015; 38:179-85. [PMID: 21251048 DOI: 10.1111/j.1440-1681.2011.05481.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
1. Chronic heart failure (CHF) is often accompanied by renal dysfunction. Exercise training may relieve the symptomatic burden and improve the overall prognosis of CHF. In the present study, the effects of exercise training on renal function and renal aquaporin (AQP)-2 expression in CHF rats were examined to determine whether exercise training could relieve renal dysfunction in CHF rats. 2. Male Sprague-Dawley rats were divided into three groups: sham, sedentary CHF (Sed-CHF) and exercise training CHF (Ex-CHF) groups. Cardiorenal function was assessed in each group by haemodynamic measurement and ultraviolet spectrophotometry. Pathological changes in cardiac and renal tissues were evaluated histologically and the collagen volume fraction (CVF) was calculated. The expressions of AQP-2 and β-tubulin were determined by western blotting and immunohistochemistry. 3. The Sed-CHF rats were found to have increased left ventricular end-diastolic pressure (LVEDP) and CVF in the heart compared with sham rats. Exercise training decreased LVEDP and CVF values in Ex-CHF rats. The Sed-CHF rats were found to have increased serum levels of creatinine (sCr), blood urea nitrogen (BUN) and arginine vasopressin (AVP), as well as increased CVF in the kidney, compared with sham rats. Exercise training decreased levels of sCr, BUN, AVP and CVF in Ex-CHF rats. Moreover, exercise training decreased AQP-2 and β-tubulin protein expression in the kidney of CHF rats. 4. The results suggest that exercise training can significantly improve the renal dysfunction in CHF rats and that the underlying mechanism may be related to water reabsorption and preventing changes to the cytoskeleton.
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Affiliation(s)
- Qin-Qin Lin
- Department of Pharmacology, Medical School of Xi'an Jiaotong University and Key Laboratory of Environment and Genes Related Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi Province, China
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Hyponatremia Associated with Heart Failure: Pathological Role of Vasopressin-Dependent Impaired Water Excretion. J Clin Med 2015; 4:933-47. [PMID: 26239456 PMCID: PMC4470207 DOI: 10.3390/jcm4050933] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 02/19/2015] [Accepted: 04/07/2015] [Indexed: 11/18/2022] Open
Abstract
An exaggerated increase in circulatory blood volume is linked to congestive heart failure. Despite this increase, reduction of the “effective circulatory blood volume” in congestive heart failure is associated with decreased cardiac output, and can weaken the sensitivity of baroreceptors. Thereafter, tonic inhibition of the baroreceptor-mediated afferent pathway of vagal nerves is removed, providing an increase in non-osmotic release of arginine vasopressin (AVP). In the renal collecting duct, the aquaporin-2 (AQP2) water channel is regulated by sustained elevation of AVP release, and this leads to augmented hydroosmotic action of AVP, that results in exaggerated water retention and dilutional hyponatremia. Hyponatremia is also a predictor for worsening heart failure in patients with known/new onset heart failure. Therefore, such a dilutional hyponatremia associated with organ damage is predictive of the short- and long-term outcome of heart failure.
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AVP-induced increase in AQP2 and p-AQP2 is blunted in heart failure during cardiac remodeling and is associated with decreased AT1R abundance in rat kidney. PLoS One 2015; 10:e0116501. [PMID: 25658446 PMCID: PMC4319737 DOI: 10.1371/journal.pone.0116501] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 12/10/2014] [Indexed: 01/02/2023] Open
Abstract
AIM The objective was to examine the renal effects of long-term increased angiotensin II and vasopressin plasma levels in early-stage heart failure (HF). We investigated the regulations of the V2 vasopressin receptor, the type 1A angiotensin II receptor, the (pro)renin receptor, and the water channels AQP2, AQP1, AQP3, and AQP4 in the inner medulla of rat kidney. METHODS HF was induced by coronary artery ligation. Sixty-eight rats were allocated to six groups: Sham (N = 11), HF (N = 11), sodium restricted sham (N = 11), sodium restricted HF (N = 11), sodium restricted sham + DDAVP (N = 12), and sodium restricted HF + DDAVP (N = 12). 1-desamino-8-D-arginine vasopressin (0.5 ng h-1 for 7 days) or vehicle was administered. Pre- and post-treatment echocardiographic evaluation was performed. The rats were sacrificed at day 17 after surgery, before cardiac remodeling in rat is known to be completed. RESULTS HF rats on standard sodium diet and sodium restriction displayed biochemical markers of HF. These rats developed hyponatremia, hypo-osmolality, and decreased fractional excretion of sodium. Increase of AQP2 and p(Ser256)-AQP2 abundance in all HF groups was blunted compared with control groups even when infused with DDAVP and despite increased vasopressin V2 receptor and Gsα abundance. This was associated with decreased protein abundance of the AT1A receptor in HF groups vs. controls. CONCLUSION Early-stage HF is associated with blunted increase in AQP2 and p(Ser256)-AQP2 despite of hyponatremia, hypo-osmolality, and increased inner medullary vasopressin V2 receptor expression. Decreased type 1A angiotensin II receptor abundance likely plays a role in the transduction of these effects.
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Hyponatremia in Acute Decompensated Heart Failure. J Am Coll Cardiol 2015; 65:480-92. [DOI: 10.1016/j.jacc.2014.12.010] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/30/2014] [Accepted: 12/02/2014] [Indexed: 01/11/2023]
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Kue-A-Pai P, Buppajarntham S. STEMI complicated with serum sodium of 113 mmol/L from syndrome of inappropriate antidiuretic hormone secretion: How worse could it be? J Cardiol Cases 2014; 10:190-192. [PMID: 30534240 DOI: 10.1016/j.jccase.2014.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 06/23/2014] [Accepted: 07/11/2014] [Indexed: 11/29/2022] Open
Abstract
Hyponatremia commonly occurs in acute coronary syndrome and has been recognized as a worse prognostic indicator in patients with ST-segment elevation myocardial infarction (STEMI). However STEMI with preexisting hyponatremia from syndrome of inappropriate antidiuretic hormone secretion (SIADH) has never been described in the literature. We describe a case of 59-year-old woman who presented with STEMI and received emergent percutaneous coronary intervention who also had SIADH with the lowest serum sodium measurement of 113 mmol/L. Initially, she was treated with hypertonic saline to reduce central nervous system complications. Then, vasopressin receptor 2 antagonist and demeclocycline were started as well as fluid restriction and salt tablet. Her sodium level and clinical symptoms improved. Subsequently, we found cavitary right upper lung mass and a biopsy report revealed small cell lung cancer as a cause of SIADH. Severe hyponatremia from SIADH complicated with STEMI could potentially have reduced adverse outcomes by normalizing sodium level through vasopressin receptor 2 antagonist or demeclocycline. <Learning objective: Hyponatremia in STEMI from SIADH, prognosis, and treatment options.>.
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Wu ZL, Ren H, Lai WY, Lin S, Jiang RY, Ye TC, Shen QB, Zeng QC, Xu DL. Sclederma of Poria cocos exerts its diuretic effect via suppression of renal aquaporin-2 expression in rats with chronic heart failure. JOURNAL OF ETHNOPHARMACOLOGY 2014; 155:563-571. [PMID: 24933223 DOI: 10.1016/j.jep.2014.05.054] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 05/27/2014] [Accepted: 05/27/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sclederma of Poria cocos (Hoelen) has been used as a diuretic in traditional Asian medicine. However, the underlying mechanism by which Sclederma of Poria cocos (hoelen) exerts its diuretic effect has not been well identified. The aim of the present study was to evaluate the effects of Sclederma of Poria cocos (hoelen) in rats with chronic heart failure (CHF) induced by acute myocardial infarction and to investigate the underlying mechanisms. MATERIALS AND METHODS An aqueous extract of Sclederma of Poria cocos (hoelen) (2.4 g/kg/d, 1.2 g/kg/d or 0.6 g/kg/d) or furosemide (20 mg/kg/d) was administered orally to male Sprague-Dawley rats starting on the day of coronary ligation. The urine output of all rats was quantified and collected every day for 1 or 4 weeks. The expression of aquaporin-2 (AQP2) was examined after treatment for 1 or 4 weeks. RESULTS Urinary output increased significantly and urinary osmolality decreased after oral administration of Sclederma of Poria cocos (hoelen) for both 1 and 4 weeks. Sclederma of Poria cocos (hoelen) caused less electrolyte disorder than furosemide. Furthermore, Sclederma of Poria cocos (hoelen) reduced the levels of plasma BNP in CHF rats, whereas furosemide had no effect. Importantly, both mRNA and protein expression of AQP2 were down-regulated and urinary excretion of AQP2 was decreased after administration of Sclederma of Poria cocos (hoelen) to CHF rats. Similarly, Sclederma of Poria cocos (hoelen) reduced plasma arginine vasopressin (AVP) level and down-regulated vasopressin type 2 receptor (V2R) mRNA expression. CONCLUSIONS Sclederma of Poria cocos (hoelen) exerts its diuretic effect and improves cardiac function in CHF rats via the AVP-V2R-AQP2 axis.
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Affiliation(s)
- Zhen-Li Wu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Ren
- Key Laboratory for Organ Failure Research, Ministry of Education of the People׳s Republic of China, China; Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wen-Yan Lai
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Key Laboratory for Organ Failure Research, Ministry of Education of the People׳s Republic of China, China
| | - Sheng Lin
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong-Yan Jiang
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tao-Chun Ye
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian-Bo Shen
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qing-Chun Zeng
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Key Laboratory for Organ Failure Research, Ministry of Education of the People׳s Republic of China, China
| | - Ding-Li Xu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Key Laboratory for Organ Failure Research, Ministry of Education of the People׳s Republic of China, China.
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Liamis G, Filippatos TD, Elisaf MS. Treatment of hyponatremia: the role of lixivaptan. Expert Rev Clin Pharmacol 2014; 7:431-41. [DOI: 10.1586/17512433.2014.911085] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Tkachenko O, Shchekochikhin D, Schrier RW. Hormones and hemodynamics in pregnancy. Int J Endocrinol Metab 2014; 12:e14098. [PMID: 24803942 PMCID: PMC4005978 DOI: 10.5812/ijem.14098] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 10/15/2013] [Accepted: 12/10/2013] [Indexed: 11/16/2022] Open
Abstract
CONTEXT Normal pregnancy is associated with sodium and water retention, which results in plasma volume expansion prior to placental implantation. The explanation offered for these events is that pregnancy 'resets' both volume and osmoreceptors. EVIDENCE ACQUISITION The mechanisms for such an enigmatic 'resetting' in pregnancy have not previously been explained. However, recent human pregnancy studies have demonstrated that the earliest hemodynamic change in pregnancy is primary systemic arterial vasodilation. This arterial underfilling is associated with a secondary increase in cardiac output and activation of the neurohumoral axis, including stimulation of the renin-angiotensin-aldosterone, sympathetic, and non-osmotic vasopressin systems. Resistance to the pressor effects of angiotensin and sympathetic stimulation in pregnancy is compatible with an increase in endothelial nitric oxide synthase activity. RESULTS In contrast to the sodium and water retention which occur secondary to the primary arterial vasodilation in cirrhosis, glomerular filtration and renal blood flow are significantly increased in normal pregnancy. A possible explanation for this difference in arterial vasodilation states is that relaxin, an arterial vasodilator which increases during pregnancy, has a potent effect on both systemic and renal circulation. Endothelial damage in pregnancy is pivotal in the pathogenesis of preeclampsia in pregnancy. CONCLUSIONS Against a background of the primary arterial vasodilation hypothesis, it is obvious that reversal of the systemic vasodilatation in pregnancy, without subsequent activation of the renin-angiotensin-aldosterone system (78), will evoke a reversal of all the links in the chain of events in normal pregnancy adaptation, thus, it may cause preeclampsia. Namely, a decrease of renal vasodilation will decrease glomerular filtration rate.
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Affiliation(s)
- Oleksandra Tkachenko
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Denver, Colorado, USA
| | - Dmitry Shchekochikhin
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Denver, Colorado, USA
| | - Robert W. Schrier
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Denver, Colorado, USA
- Corresponding author: Robert W. Schrier, Department of Medicine, University of Colorado, 12700 East 19th Avenue C281, Aurora, CO 80045, USA. Tel: +1-3037244837, Fax: +1-3037244868, E-mail:
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Schwarz ER, Sanghi P. Conivaptan: a selective vasopressin antagonist for the treatment of heart failure. Expert Rev Cardiovasc Ther 2014; 4:17-23. [PMID: 16375624 DOI: 10.1586/14779072.4.1.17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Heart failure commonly manifests as a syndrome of salt and water retention. Arginine vasopressin plays an important role in volume homeostasis and may contribute to this syndrome seen in heart failure patients. Recently, a number of agents have been developed that antagonize the effects of vasopressin. Conivaptan, which is a dual antagonist of the V1a and V2 receptor, has shown promise in animal studies and in small scale human trials as a potential therapeutic option for the treatment of acute and chronic heart failure. Further large studies are being conducted, which may confirm the benefits of conivaptan and other vasopressin antagonists in heart failure patients.
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Affiliation(s)
- Ernst R Schwarz
- Division of Cardiology, Department of Internal Medicine, The University of Texas Medical Branch School of Medicine, Galveston, TX 77555-0553, USA.
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Burnatowska-Hledin MA, Barney CC. New insights into the mechanism for VACM-1/cul5 expression in vascular tissue in vivo. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2014; 313:79-101. [PMID: 25376490 DOI: 10.1016/b978-0-12-800177-6.00003-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Vasopressin-activated calcium-mobilizing (VACM-1)/cul5 is the least conserved member of a cullin protein family involved in the formation of E3-specific ligase complexes that are responsible for delivering the ubiquitin protein to their target substrate proteins selected for ubiquitin-dependent degradation. This chapter summarizes work to date that has focused on VACM-1/cul5's tissue-specific expression in vivo and on its potential role in the control of specific cellular signaling pathways in those structures. As mammalian cells may contain hundreds of E3 ligases, identification VACM-1/cul5 as a specific subunit of the system that is expressed in the endothelium and in collecting tubules, structures known for their control of cellular permeability, may have significant implications when designing studies to elucidate the mechanism of water conservation. For example, VACM-1/cul5 expression is affected by water deprivation in some tissues and there is a potential relationship between neddylated VACM-1/cul5 and aquaporins.
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Affiliation(s)
- Maria A Burnatowska-Hledin
- Department of Biology, Hope College, Holland, MI, USA; Department of Chemistry, Hope College, Holland, MI, USA
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Abstract
Aquaporins (AQPs) are a family of membrane water channels that basically function as regulators of intracellular and intercellular water flow. To date, thirteen aquaporins have been characterized. They are distributed wildly in specific cell types in multiple organs and tissues. Each AQP channel consists of six membrane-spanning alpha-helices that have a central water-transporting pore. Four AQP monomers assemble to form tetramers, which are the functional units in the membrane. Some of AQPs also transport urea, glycerol, ammonia, hydrogen peroxide, and gas molecules. AQP-mediated osmotic water transport across epithelial plasma membranes facilitates transcellular fluid transport and thus water reabsorption. AQP-mediated urea and glycerol transport is involved in energy metabolism and epidermal hydration. AQP-mediated CO2 and NH3 transport across membrane maintains intracellular acid-base homeostasis. AQPs are also involved in the pathophysiology of a wide range of human diseases (including water disbalance in kidney and brain, neuroinflammatory disease, obesity, and cancer). Further work is required to determine whether aquaporins are viable therapeutic targets or reliable diagnostic and prognostic biomarkers.
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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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