|
1
|
Beke E, Gondran C, Chovelon B, Peyrin E, Holzinger M, Ravelet C. Aptamers and MIPs as alternative molecular recognition elements for vasopressin and oxytocin sensing: A review. Biosens Bioelectron 2025; 278:117306. [PMID: 40023907 DOI: 10.1016/j.bios.2025.117306] [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: 02/27/2024] [Revised: 02/15/2025] [Accepted: 02/22/2025] [Indexed: 03/04/2025]
Abstract
Arginine vasopressin (AVP) and oxytocin (OT) are two important hormones that regulate various physiological and behavioral functions, such as blood pressure, water balance, social bonding, and stress response. The detection and quantification of these hormones are of great interest in clinical diagnosis and research. However, the conventional methods based on antibodies or enzymes have some limitations, such as high cost, low stability, and ethical issues. Therefore, alternative molecular recognition elements, such as aptamers and molecularly imprinted polymers (MIPs), have been developed to overcome these drawbacks. Aptamers are short nucleic acid sequences that can bind to specific targets with high affinity and specificity, while MIPs are synthetic polymers with imprinted binding sites mimicking natural receptors. Both aptamers and MIPs have advantages such as low cost, high stability, easy synthesis, and modification. In this review, we summarize the recent advances in the development and application of aptamers and MIPs for the sensing of vasopressin and oxytocin, and compare their performances. We also discuss the challenges and future perspectives of aptamers and MIPs as alternative molecular recognition elements for vasopressin and oxytocin sensing.
Collapse
Affiliation(s)
- Essohanam Beke
- University Grenoble Alpes-CNRS, DCM, UMR, 5250, Grenoble, France; University Grenoble Alpes, DPM, UMR, 5063, Grenoble, France
| | - Chantal Gondran
- University Grenoble Alpes-CNRS, DCM, UMR, 5250, Grenoble, France.
| | - Benoît Chovelon
- University Grenoble Alpes, DPM, UMR, 5063, Grenoble, France; Biochemistry Department, Grenoble Alpes University Hospital - Biology and Pathology Institute, F-38041, Grenoble, France
| | - Eric Peyrin
- University Grenoble Alpes, DPM, UMR, 5063, Grenoble, France
| | | | - Corinne Ravelet
- University Grenoble Alpes, DPM, UMR, 5063, Grenoble, France.
| |
Collapse
|
|
2
|
Castagna A, Mango G, Martinelli N, Marzano L, Moruzzi S, Friso S, Pizzolo F. Sodium Chloride Cotransporter in Hypertension. Biomedicines 2024; 12:2580. [PMID: 39595146 PMCID: PMC11591633 DOI: 10.3390/biomedicines12112580] [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: 10/07/2024] [Revised: 10/29/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
The sodium chloride cotransporter (NCC) is essential for electrolyte balance, blood pressure regulation, and pathophysiology of hypertension as it mediates the reabsorption of ultrafiltered sodium in the renal distal convoluted tubule. Given its pivotal role in the maintenance of extracellular fluid volume, the NCC is regulated by a complex network of cellular pathways, which eventually results in either its phosphorylation, enhancing sodium and chloride ion absorption from urines, or dephosphorylation and ubiquitination, which conversely decrease NCC activity. Several factors could influence NCC function, including genetic alterations, hormonal stimuli, and pharmacological treatments. The NCC's central role is also highlighted by several abnormalities resulting from genetic mutations in its gene and consequently in its structure, leading to dysregulation of blood pressure control. In the last decade, among other improvements, the acquisition of knowledge on the NCC and other renal ion channels has been favored by studies on extracellular vesicles (EVs). Dietary sodium and potassium intake are also implicated in the tuning of NCC activity. In this narrative review, we present the main cornerstones and recent evidence related to NCC control, focusing on the context of blood pressure pathophysiology, and promising new therapeutical approaches.
Collapse
Affiliation(s)
- Annalisa Castagna
- Department of Medicine, University of Verona, 37134 Verona, Italy; (A.C.); (G.M.); (N.M.); (S.F.)
| | - Gabriele Mango
- Department of Medicine, University of Verona, 37134 Verona, Italy; (A.C.); (G.M.); (N.M.); (S.F.)
| | - Nicola Martinelli
- Department of Medicine, University of Verona, 37134 Verona, Italy; (A.C.); (G.M.); (N.M.); (S.F.)
| | - Luigi Marzano
- Unit of Internal Medicine B, Department of Medicine, University of Verona School of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Policlinico “G.B. Rossi”, 37134 Verona, Italy; (L.M.); (S.M.)
| | - Sara Moruzzi
- Unit of Internal Medicine B, Department of Medicine, University of Verona School of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Policlinico “G.B. Rossi”, 37134 Verona, Italy; (L.M.); (S.M.)
| | - Simonetta Friso
- Department of Medicine, University of Verona, 37134 Verona, Italy; (A.C.); (G.M.); (N.M.); (S.F.)
| | - Francesca Pizzolo
- Department of Medicine, University of Verona, 37134 Verona, Italy; (A.C.); (G.M.); (N.M.); (S.F.)
| |
Collapse
|
|
3
|
Ciortea DA, Petrea (Cliveți) CL, Berbece SI, Fotea S, Vivisenco IC, Gurău G, Matei MN, Nechita A. Impact of Hyponatremia and ADH Secretion in MIS-C and COVID-19: An Integrative Approach of Prognostic and Diagnostic Markers. Curr Issues Mol Biol 2024; 46:11749-11771. [PMID: 39590292 PMCID: PMC11592771 DOI: 10.3390/cimb46110698] [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: 09/11/2024] [Revised: 10/18/2024] [Accepted: 10/19/2024] [Indexed: 11/28/2024] Open
Abstract
The COVID-19 pandemic has introduced challenges in pediatric care, especially due to the emergence of Multisystem Inflammatory Syndrome in Children (MIS-C), a severe condition associated with SARS-CoV-2 infection. This study investigated the impact of hyponatremia and antidiuretic hormone (ADH) secretion corelated to clinical outcomes in these patients. We conducted a retrospective cohort study, including 118 pediatric patients, with a detailed sub-cohort analysis of 53 patients for ADH secretion markers. Hyponatremia, defined by age-specific sodium thresholds, was present in 47.22% of MIS-C cases and 28.04% of COVID-19 cases. Ordinal logistic regression analysis revealed that severe hyponatremia significantly increased the likelihood of more severe clinical outcomes (β = 3.514, p < 0.001). A significant correlation was found between hyponatremia and prolonged hospitalization. For ADH secretion, a predictive model using ridge regression was analysed, which demonstrated that serum sodium level, U/P ratio, and hospitalization duration are key predictors of SIADH. This model fit was assessed using the ROC curve with an AUC of 0.96, indicating reliable model performance. Our findings underscore the significant role of hyponatremia on the clinical severity and hospitalization outcome of COVID-19 and MIS-C in pediatric patients.
Collapse
Affiliation(s)
- Diana-Andreea Ciortea
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
- Emergency Clinical Hospital for Children “Maria Sklodowska Curie”, 041451 Bucharest, Romania
| | - Carmen Loredana Petrea (Cliveți)
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Sorin Ion Berbece
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
| | - Silvia Fotea
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Iolanda Cristina Vivisenco
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 030167 Bucharest, Romania;
- Department of Pediatrics, Emergency Clinical Hospital for Children “Grigore Alexandrescu”, 011743 Bucharest, Romania
| | - Gabriela Gurău
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Mădălina Nicoleta Matei
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Aurel Nechita
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800201 Galati, Romania; (D.-A.C.); (C.L.P.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| |
Collapse
|
|
4
|
Chapman FA, Melville V, Godden E, Morrison B, Bruce L, Maguire JJ, Davenport AP, Newby DE, Dhaun N. Cardiovascular and renal effects of apelin in chronic kidney disease: a randomised, double-blind, placebo-controlled, crossover study. Nat Commun 2024; 15:8387. [PMID: 39402039 PMCID: PMC11473822 DOI: 10.1038/s41467-024-52447-7] [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: 03/21/2024] [Accepted: 09/09/2024] [Indexed: 10/17/2024] Open
Abstract
Chronic kidney disease (CKD) affects ~10% of the population and cardiovascular disease is its commonest complication. Despite treatment, patient outcomes remain poor and newer therapies are urgently needed. Here, we investigated the systemic and renal effects of apelin in CKD. In a randomized, double-blind, placebo-controlled, crossover study, 24 subjects (12 patients with CKD and 12 matched healthy subjects) received pyroglutamated apelin-13 ([Pyr1]apelin-13, 1 nmol/min and 30 nmol/min) or matched placebo on two separate visits. Systemic and renal hemodynamics were monitored throughout. The co-primary endpoints were change in systemic vascular resistance index and renal blood flow. Secondary endpoints were change in blood pressure, cardiac output, pulse wave velocity, glomerular filtration rate, natriuresis, free water clearance and urinary protein excretion. In both health and CKD, 30 nmol/min [Pyr1]apelin-13 reduced mean arterial pressure by ~4%, systemic vascular resistance by ~12%, and increased cardiac index by ~10%, compared to placebo (p < 0.05 for all). Both doses of [Pyr1]apelin-13 increased renal blood flow by ~15%, natriuresis by ~20% and free water clearance by ~10%, compared to placebo (p < 0.05 for all). In patients with chronic kidney disease only, glomerular filtration rate fell by ~10%, effective filtration fraction by ~5% and proteinuria by ~25% (p < 0.01 for all). Apelin has short-term cardiovascular and renal benefits in CKD. If maintained longer-term, these should improve patient outcomes. Clinical trials of long-acting oral apelin agonists are justified in CKD and other conditions with impaired salt and water balance. Registration number at www.clinicalTrials.gov : NCT03956576. Funded by Kidney Research UK.
Collapse
Affiliation(s)
- Fiona A Chapman
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Vanessa Melville
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Emily Godden
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Beth Morrison
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Lorraine Bruce
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Janet J Maguire
- Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, UK
| | - Anthony P Davenport
- Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, UK
| | - David E Newby
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neeraj Dhaun
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
| |
Collapse
|
|
5
|
Wu L, Rodriguez M, El Hachem K, Krittanawong C. Diuretic Treatment in Heart Failure: A Practical Guide for Clinicians. J Clin Med 2024; 13:4470. [PMID: 39124738 PMCID: PMC11313642 DOI: 10.3390/jcm13154470] [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: 07/09/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Congestion and fluid retention are the hallmarks of decompensated heart failure and the major reason for the hospitalization of patients with heart failure. Diuretics have been used in heart failure for decades, and they remain the backbone of the contemporary management of heart failure. Loop diuretics is the preferred diuretic, and it has been given a class I recommendation by clinical guidelines for the relief of congestion symptoms. Although loop diuretics have been used virtually among all patients with acute decompensated heart failure, there is still very limited clinical evidence to guide the optimized diuretics use. This is a sharp contrast to the rapidly growing evidence of the rest of the guideline-directed medical therapy of heart failure and calls for further studies. The loop diuretics possess a unique pharmacology and pharmacokinetics that lay the ground for different strategies to increase diuretic efficiency. However, many of these approaches have not been evaluated in randomized clinical trials. In recent years, a stepped and protocolized diuretics dosing has been suggested to have superior benefits over an individual clinician-based strategy. Diuretic resistance has been a major challenge to decongestion therapy for patients with heart failure and is associated with a poor clinical prognosis. Recently, therapy options have emerged to help overcome diuretic resistance to loop diuretics and have been evaluated in randomized clinical trials. In this review, we aim to provide a comprehensive review of the pharmacology and clinical use of loop diuretics in the context of heart failure, with attention to its side effects, and adjuncts, as well as the challenges and future direction.
Collapse
Affiliation(s)
- Lingling Wu
- Cardiovascular Division, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Mario Rodriguez
- John T. Milliken Department of Medicine, Division of Cardiovascular Disease, Section of Advanced Heart Failure and Transplant, Barnes-Jewish Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
| | - Karim El Hachem
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY 10029, USA
| | - Chayakrit Krittanawong
- Section of Cardiology, Cardiology Division, NYU Langone Health and NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA
| |
Collapse
|
|
6
|
Soares AG, Contreras J, Mironova E, Archer CR, Stockand JD, Abd El-Aziz TM. P2Y2 receptor decreases blood pressure by inhibiting ENaC. JCI Insight 2023; 8:e167704. [PMID: 37279066 PMCID: PMC10443811 DOI: 10.1172/jci.insight.167704] [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: 12/01/2022] [Accepted: 06/02/2023] [Indexed: 06/07/2023] Open
Abstract
Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to participate in P2ry2 effects on blood pressure. To isolate the role of the kidneys in P2ry2 effects on blood pressure and to reveal the molecular and cellular mechanisms of this action, we test here the necessity of the P2ry2 and the sufficiency of Gq-dependent signaling in renal principal cells to the regulation of the epithelial Na+ channel (ENaC), sodium excretion, and blood pressure. Activating P2ry2 in littermate controls but not principal cell-specific P2ry2-knockout mice decreased the activity of ENaC in renal tubules. Moreover, deletion of P2ry2 in principal cells abolished increases in sodium excretion in response to stimulation of P2ry2 and compromised the normal ability to excrete a sodium load. Consequently, principal cell-specific knockout of P2ry2 prevented decreases in blood pressure in response to P2ry2 stimulation in the deoxycorticosterone acetate-salt (DOCA-salt) model of hypertension. In wild-type littermate controls, such stimulation decreased blood pressure in this model of hypertension by promoting a natriuresis. Pharmacogenetic activation of Gq exclusively in principal cells using targeted expression of Gq-designer receptors exclusively activated by designer drugs and clozapine N-oxide decreased the activity of ENaC in renal tubules, promoting a natriuresis that lowered elevated blood pressure in the DOCA-salt model of hypertension. These findings demonstrate that the kidneys play a major role in decreasing blood pressure in response to P2ry2 activation and that inhibition of ENaC activity in response to P2ry2-mediated Gq signaling lowered blood pressure by increasing renal sodium excretion.
Collapse
Affiliation(s)
- Antonio G. Soares
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Jorge Contreras
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Elena Mironova
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Crystal R. Archer
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - James D. Stockand
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Tarek Mohamed Abd El-Aziz
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
- Zoology Department, Faculty of Science, Minia University, El-Minia, Egypt
| |
Collapse
|
|
7
|
Sodium Homeostasis, a Balance Necessary for Life. Nutrients 2023; 15:nu15020395. [PMID: 36678265 PMCID: PMC9862583 DOI: 10.3390/nu15020395] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated levels of this solute (hypernatremia), as in diabetes insipidus, but also reduced levels (hyponatremia), as in cerebral salt wasting syndrome. The balance in body Na levels therefore requires a delicate equilibrium to be maintained between the ingestion and excretion of Na. Salt (NaCl) intake is processed by receptors in the tongue and digestive system, which transmit the information to the nucleus of the solitary tract via a neural pathway (chorda tympani/vagus nerves) and to circumventricular organs, including the subfornical organ and area postrema, via a humoral pathway (blood/cerebrospinal fluid). Circuits are formed that stimulate or inhibit homeostatic Na intake involving participation of the parabrachial nucleus, pre-locus coeruleus, medial tuberomammillary nuclei, median eminence, paraventricular and supraoptic nuclei, and other structures with reward properties such as the bed nucleus of the stria terminalis, central amygdala, and ventral tegmental area. Finally, the kidney uses neural signals (e.g., renal sympathetic nerves) and vascular (e.g., renal perfusion pressure) and humoral (e.g., renin-angiotensin-aldosterone system, cardiac natriuretic peptides, antidiuretic hormone, and oxytocin) factors to promote Na excretion or retention and thereby maintain extracellular fluid volume. All these intake and excretion processes are modulated by chemical messengers, many of which (e.g., aldosterone, angiotensin II, and oxytocin) have effects that are coordinated at peripheral and central level to ensure Na homeostasis.
Collapse
|
|
8
|
The Relationship between the Plasma Concentration of Electrolytes and Intensity of Sleep Bruxism and Blood Pressure Variability among Sleep Bruxers. Biomedicines 2022; 10:biomedicines10112804. [PMID: 36359324 PMCID: PMC9687451 DOI: 10.3390/biomedicines10112804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/28/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
Plasma sodium plays a major role in regulating blood pressure (BP). An augmented variability of BP is considered a risk factor for the development of arterial hypertension, which is prevalent among patients with suspected sleep bruxism (SB). The aims of this study were to assess the plasma concentration of electrolytes and their effect on the intensity of SB and BP variability among sleep bruxers. A total of 51 patients were enrolled in this prospective, observational study. A single full-night polysomnographic examination was conducted in the Wroclaw Medical University Sleep Laboratory, Poland, and based on the guidelines of the American Academy of Sleep Medicine, the results were analyzed. The monitoring of ambulatory BP was performed the next day, and the plasma levels of sodium, potassium, magnesium, and calcium were measured. The mean age of the studied group was 33.9 ± 11.2 years, and the mean bruxism episode index (BEI) was 4.94 ± 3.53. The study revealed statistically significant differences in the plasma concentrations of sodium in the SB group. A decreased sodium concentration was observed in the group of mild bruxers (2 ≤ BEI < 4) (139.7 ± 1.4 vs. 142.8 ± 3.2, p = 0.002) and severe bruxers (BEI ≥ 4) (140.5 ± 2.0 vs. 142.8 ± 3.2, p = 0.016) compared to nonbruxers (BEI < 2). A statistically significant positive linear correlation was found between plasma sodium concentration and daytime systolic BP variability (r = 0.32, p < 0.05) as well as between plasma sodium concentration and nighttime diastolic BP variability (r = 0.31, p < 0.05). The preliminary results suggest the probable relationship between the lower plasma concentration of sodium and increased intensity of SB and BP variability among suspected sleep bruxers.
Collapse
|
|
9
|
Chang DC, Penesova A, Bunt JC, Stinson EJ, Kavouras SA, Gluck ME, Paddock E, Walter M, Piaggi P, Krakoff J. Water intake, thirst, and copeptin responses to two dehydrating stimuli in lean men and men with obesity. Obesity (Silver Spring) 2022; 30:1806-1817. [PMID: 35918877 PMCID: PMC9420804 DOI: 10.1002/oby.23520] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity. METHODS Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed. RESULTS After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity. CONCLUSIONS Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation.
Collapse
Affiliation(s)
- Douglas C. Chang
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Adela Penesova
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Joy C. Bunt
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Emma J. Stinson
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | | | - Marci E. Gluck
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Ethan Paddock
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Mary Walter
- Clinical Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Paolo Piaggi
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Jonathan Krakoff
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| |
Collapse
|
|
10
|
Szczepanska-Sadowska E, Wsol A, Cudnoch-Jedrzejewska A, Żera T. Complementary Role of Oxytocin and Vasopressin in Cardiovascular Regulation. Int J Mol Sci 2021; 22:11465. [PMID: 34768894 PMCID: PMC8584236 DOI: 10.3390/ijms222111465] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/17/2022] Open
Abstract
The neurons secreting oxytocin (OXY) and vasopressin (AVP) are located mainly in the supraoptic, paraventricular, and suprachiasmatic nucleus of the brain. Oxytocinergic and vasopressinergic projections reach several regions of the brain and the spinal cord. Both peptides are released from axons, soma, and dendrites and modulate the excitability of other neuroregulatory pathways. The synthesis and action of OXY and AVP in the peripheral organs (eye, heart, gastrointestinal system) is being investigated. The secretion of OXY and AVP is influenced by changes in body fluid osmolality, blood volume, blood pressure, hypoxia, and stress. Vasopressin interacts with three subtypes of receptors: V1aR, V1bR, and V2R whereas oxytocin activates its own OXTR and V1aR receptors. AVP and OXY receptors are present in several regions of the brain (cortex, hypothalamus, pons, medulla, and cerebellum) and in the peripheral organs (heart, lungs, carotid bodies, kidneys, adrenal glands, pancreas, gastrointestinal tract, ovaries, uterus, thymus). Hypertension, myocardial infarction, and coexisting factors, such as pain and stress, have a significant impact on the secretion of oxytocin and vasopressin and on the expression of their receptors. The inappropriate regulation of oxytocin and vasopressin secretion during ischemia, hypoxia/hypercapnia, inflammation, pain, and stress may play a significant role in the pathogenesis of cardiovascular diseases.
Collapse
Affiliation(s)
- Ewa Szczepanska-Sadowska
- Laboratory of Centre for Preclinical Research, Chair and Department of Experimental and Clinical Physiology, Medical University of Warsaw, 02-091 Warsaw, Poland; (A.W.); (A.C.-J.); (T.Ż.)
| | | | | | | |
Collapse
|
|
11
|
Soares AG, Contreras J, Archer CR, Mironova E, Berdeaux R, Stockand JD, Abd El-Aziz TM. Stimulation of the Epithelial Na + Channel in Renal Principal Cells by Gs-Coupled Designer Receptors Exclusively Activated by Designer Drugs. Front Physiol 2021; 12:725782. [PMID: 34512393 PMCID: PMC8425396 DOI: 10.3389/fphys.2021.725782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/28/2021] [Indexed: 11/29/2022] Open
Abstract
The activity of the Epithelial Na+ Channel (ENaC) in renal principal cells (PC) fine-tunes sodium excretion and consequently, affects blood pressure. The Gs-adenylyl cyclase-cAMP signal transduction pathway is believed to play a central role in the normal control of ENaC activity in PCs. The current study quantifies the importance of this signaling pathway to the regulation of ENaC activity in vivo using a knock-in mouse that has conditional expression of Gs-DREADD (designer receptors exclusively activated by designer drugs; GsD) in renal PCs. The GsD mouse also contains a cAMP response element-luciferase reporter transgene for non-invasive bioluminescence monitoring of cAMP signaling. Clozapine N-oxide (CNO) was used to selectively and temporally stimulate GsD. Treatment with CNO significantly increased luciferase bioluminescence in the kidneys of PC-specific GsD but not control mice. CNO also significantly increased the activity of ENaC in principal cells in PC-specific GsD mice compared to untreated knock-in mice and CNO treated littermate controls. The cell permeable cAMP analog, 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate, significantly increased the activity and expression in the plasma membrane of recombinant ENaC expressed in CHO and COS-7 cells, respectively. Treatment of PC-specific GsD mice with CNO rapidly and significantly decreased urinary Na+ excretion compared to untreated PC-specific GsD mice and treated littermate controls. This decrease in Na+ excretion in response to CNO in PC-specific GsD mice was similar in magnitude and timing as that induced by the selective vasopressin receptor 2 agonist, desmopressin, in wild type mice. These findings demonstrate for the first time that targeted activation of Gs signaling exclusively in PCs is sufficient to increase ENaC activity and decrease dependent urinary Na+ excretion in live animals.
Collapse
Affiliation(s)
- Antonio G Soares
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jorge Contreras
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Crystal R Archer
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Elena Mironova
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Rebecca Berdeaux
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - James D Stockand
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Tarek Mohamed Abd El-Aziz
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Zoology Department, Faculty of Science, Minia University, Minya, Egypt
| |
Collapse
|
|
12
|
Rodriguez-Giustiniani P, Rodriguez-Sanchez N, Galloway SDR. Fluid and electrolyte balance considerations for female athletes. Eur J Sport Sci 2021; 22:697-708. [PMID: 34121620 DOI: 10.1080/17461391.2021.1939428] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
This review explores the effects of oestrogen and progesterone fluctuations across the menstrual cycle on fluid and electrolyte balance. The review aims to provide information on this topic for the exercising female but also for researchers working in this field. Beginning with a basic introduction to fluid and electrolyte balance, the review goes on to describe how oestrogen and progesterone have independent and integrated roles to play in the regulation of fluid and electrolyte balance. Despite evidence that oestrogen can influence the osmotic threshold for arginine vasopressin release, and that progesterone can influence aldosterone production, these actions do not appear to influence fluid retention, plasma volume changes at rest and during exercise, or electrolyte losses. However, the large inter-individual variations in hormonal fluctuations throughout the menstrual cycle may mean that specific individuals with high fluctuations could experience disturbances in their fluid and electrolyte balance. During phases of oestrogen dominance (e.g. late-follicular phase) heat dissipation is promoted, while progesterone dominance (e.g. mid-luteal phase) promotes heat conservation with overall higher basal body temperature. However, these responses do not consistently lead to any change in observed sweat rates, heat-stress, or dehydration during exercise. Finally, the literature does not support any difference in fluid retention during post-exercise rehydration periods conducted at different menstrual cycle phases. Although these mean responses largely reveal no effects on fluid and electrolyte balance, further research is required particularly in those individuals who experience high hormonal fluctuations, and greater exploration of oestrogen to progesterone interactions is warranted.
Collapse
Affiliation(s)
- Paola Rodriguez-Giustiniani
- Physiology, Exercise, and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, United Kingdom
| | - Nidia Rodriguez-Sanchez
- Physiology, Exercise, and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, United Kingdom
| | - Stuart D R Galloway
- Physiology, Exercise, and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, United Kingdom
| |
Collapse
|
|
13
|
Constanthin PE, Isidor N, de Seigneux S, Momjian S. Increased oxytocin release precedes hyponatremia after pituitary surgery. Pituitary 2021; 24:420-428. [PMID: 33506439 PMCID: PMC8119398 DOI: 10.1007/s11102-020-01121-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/26/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a well-known complication of transsphenoidal pituitary surgery, related to inappropriate secretion of arginine vasopressin (AVP). Its diagnosis is based on hyponatremia, with a peak of occurrence around day 7 after surgery and, to date, no early marker has been reported. In particular, copeptin levels are not predictive of hyponatremia in this case. Oxytocin (OXT) is secreted into the peripheral blood by axon terminals adjacent to those of AVP neurons in the posterior pituitary. Besides its role in childbirth and lactation, recent evidences suggested a role for OXT in sodium balance. The contribution of this hormone in the dysnatremias observed after pituitary surgery has however never been investigated. METHODS We analyzed the urinary output of OXT in patients subjected to transsphenoidal pituitary surgery. RESULTS While OXT excretion remained stable in patients who presented a normonatremic postoperative course, patients who were later diagnosed with SIADH-related hyponatremia presented with a significantly increased urinary secretion of OXT 4 days after surgery. CONCLUSION Taken together, these results show for the first time that urinary OXT output remains normally stable after transsphenoidal pituitary surgery. OXT excretion however becomes abnormally high on or around 4 days after surgery in patients later developing hyponatremia, suggesting that this abnormal dynamics of OXT secretion might serve as an early marker for transsphenoidal surgery-related hyponatremia attributed to SIADH.
Collapse
Affiliation(s)
- Paul Eugène Constanthin
- Department of Neurosurgery, Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland
- Faculty of Medicine, Université de Genève (UNIGE), Geneva, Switzerland
| | - Nathalie Isidor
- Clinical Investigation Unit, Clinical Research Center, University of Geneva, Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland
| | - Sophie de Seigneux
- Department of Nephrology, Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland
| | - Shahan Momjian
- Department of Neurosurgery, Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland.
- Faculty of Medicine, Université de Genève (UNIGE), Geneva, Switzerland.
| |
Collapse
|
|
14
|
Peng W, Xie Y, Liu K, Qi H, Liu Z, Xia J, Cao H, Guo C, Sun Y, Liu X, Li B, Wen F, Zhang F, Zhang L. Discrepant acute effect of saline loading on blood pressure, urinary sodium and potassium according to salt intake level: EpiSS study. J Clin Hypertens (Greenwich) 2020; 23:289-300. [PMID: 33220161 PMCID: PMC8029760 DOI: 10.1111/jch.14106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/22/2020] [Accepted: 11/02/2020] [Indexed: 11/28/2022]
Abstract
Acute dietary salt intake may cause an elevation in blood pressure (BP). The study aimed to assess the acute effect of saline loading on BP in subjects with different levels of salt intake. This study is based on the baseline survey of systemic epidemiology of salt sensitivity study. The sodium excretion in the 24-hour urine was calculated for estimating the level of salt intake. Subjects were performed an acute oral saline loading test (1 L), and data of 2019 participants were included for analyses. Multivariate linear regression and stratified analyses were performed to identify associations between 24-hour urinary sodium (24hUNa) with BP changes. Due to saline loading, systolic BP (SBP), pulse pressure, and urinary sodium concentration were significantly increased, while diastolic BP, heart rate, and urinary potassium concentration were significantly decreased. The SBP increments were more significant in subjects with lower salt intake, normotensives, elders, males, smokers, and drinkers. There was a significant linear negative dose-response association between SBP increment with 24hUNa (β = -0.901, 95% CI: -1.253, -0.548), especially in lower salt intake individuals (β = -1.297, 95% CI: -2.338, -0.205) and hypertensive patients (β = -1.502, 95% CI: -2.037, -0.967). After excluding patients who received antidiabetic or antihypertensive medicines, the effects of negative associations weakened but remained significantly. In conclusion, acute salt loading leads to an increment in SBP, and the increased SBP was negatively related with 24hUNa. This study indicated avoiding acute salt loading was important for escaping acute BP changes, especially in lower salt intake populations.
Collapse
Affiliation(s)
- Wenjuan Peng
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Yunyi Xie
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Kuo Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Han Qi
- The National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, The Advanced Innovation Center for Human Brain Protection, Beijing Anding Hospital, School of Mental Health, Capital Medical University, Beijing, China
| | - Zheng Liu
- Science Department, Peking University People's Hospital, Beijing, China
| | - Juan Xia
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Han Cao
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Chunyue Guo
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Yanyan Sun
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Xiaohui Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Bingxiao Li
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Fuyuan Wen
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Fengxu Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| | - Ling Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China
| |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
Albertoni Borghese MF, Ortiz MDC, Marinoni RC, Oronel LH, Palamidessi M, Yarza CA, Di Siervi N, Davio C, Majowicz MP. Inhibition of Endothelin system during the postnatal nephrogenic period in the rat. Its relationship with hypertension and renal disease in adulthood. PLoS One 2020; 15:e0229756. [PMID: 32126132 PMCID: PMC7053749 DOI: 10.1371/journal.pone.0229756] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 02/12/2020] [Indexed: 12/26/2022] Open
Abstract
The aim of this work was to study the effect of a high sodium (HS) diet on blood pressure and renal function in male adult rats that have been treated with a dual Endothelin receptor antagonist (ERA) during their early postnatal period (day 1 to 20 of life). Male Sprague-Dawley rats were divided in four groups: CNS: control rats with normosodic diet; ERANS: ERA-treated rats with normosodic diet; CHS: control rats with high sodium diet; ERAHS: ERA-treated rats with HS diet. Systolic blood pressure (SBP) was recorded before and after the diet and 24-hour metabolic cage studies were performed. AQP2 and α-ENac expressions were measured by western blot and real time PCR in the renal medulla. Vasopressin (AVP) pathway was evaluated by measuring V2 receptor and adenylyl cyclase 6 (AC6) expression and cAMP production in the renal medulla. Pre-pro ET-1mRNA was also evaluated in the renal medulla. Only rats that had been treated with an ERA during their postnatal period increased their SBP after consumption of a HS diet, showing an impaired capacity to excrete sodium and water, i.e. developing salt sensitivity. This salt sensitivity would be mediated by an increase in renomedullary expression and activity of AQP2 and α-ENaC as a consequence of increased AC6 expression and cAMP production and/or a decreased ET-1 production in the renal medulla. The knowledge of the molecular mechanisms underlying the perinatal programming of salt sensitive hypertension will allow the development of reprogramming strategies in order to avoid this pathology.
Collapse
Affiliation(s)
- María Florencia Albertoni Borghese
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María del Carmen Ortiz
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Rocío C. Marinoni
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Lucas H. Oronel
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Milena Palamidessi
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carolina A. Yarza
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Nicolás Di Siervi
- CONICET, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Davio
- CONICET, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA), Universidad de Buenos Aires, Buenos Aires, Argentina
- Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mónica P. Majowicz
- Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- * E-mail:
| |
Collapse
|
|
17
|
Natochin YV, Golosova DV. Vasopressin receptor subtypes and renal sodium transport. VITAMINS AND HORMONES 2019; 113:239-258. [PMID: 32138950 DOI: 10.1016/bs.vh.2019.08.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In mammals, three subtypes of V-receptors have been identified in the kidney. The effects of vasopressin, a hormone synthesized in the hypothalamus, are triggered by three distinct receptor isoforms: V2, V1a, and V1b. Stimulation of V2-receptors regulates urine osmotic concentration by increasing sodium reabsorption in the thick ascending limb of the loop of Henle and enhancing osmotic permeability of the epithelium cells in the collecting duct. Stimulation of V1a-receptors inhibits renal sodium reabsorption and induces natriuresis, comparable to the effect of the diuretic furosemide, in the thick ascending limb of the loop of Henle. Stimulation of V1b-receptors induces potassium secretion in the final parts of the distal segments and initial parts of the collecting ducts. In this review, we discuss the role of vasopressin and its interaction with V-receptor subtypes in natriuresis and for stabilizing the physicochemical parameters of the internal environment and water-salt homeostasis in humans. A better understanding of these systems and their regulation is necessary to facilitate identification of additional system components and mechanisms, clarify their contribution during various normal and pathological functional states, and suggest novel strategies for the development of therapeutic interventions.
Collapse
Affiliation(s)
- Yu V Natochin
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia.
| | - D V Golosova
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia
| |
Collapse
|
|
18
|
García-Arroyo FE, Gonzaga G, Muñoz-Jiménez I, Osorio-Alonso H, Iroz A, Vecchio M, Tapia E, Roncal-Jiménez CA, Johnson RJ, Sánchez-Lozada LG. Antioxidant supplements as a novel mean for blocking recurrent heat stress-induced kidney damage following rehydration with fructose-containing beverages. Free Radic Biol Med 2019; 141:182-191. [PMID: 31212064 DOI: 10.1016/j.freeradbiomed.2019.06.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/22/2019] [Accepted: 06/14/2019] [Indexed: 12/20/2022]
Abstract
Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well.
Collapse
Affiliation(s)
| | - Guillermo Gonzaga
- Lab. Renal Physiopathology, Dept. of Nephrology, INC Ignacio Chávez. Mexico City, Mexico
| | - Itzel Muñoz-Jiménez
- Lab. Renal Physiopathology, Dept. of Nephrology, INC Ignacio Chávez. Mexico City, Mexico
| | - Horacio Osorio-Alonso
- Lab. Renal Physiopathology, Dept. of Nephrology, INC Ignacio Chávez. Mexico City, Mexico
| | | | | | - Edilia Tapia
- Lab. Renal Physiopathology, Dept. of Nephrology, INC Ignacio Chávez. Mexico City, Mexico
| | | | - Richard J Johnson
- Renal Diseases and Hypertension. University of Colorado. Aurora CO, USA
| | - Laura G Sánchez-Lozada
- Lab. Renal Physiopathology, Dept. of Nephrology, INC Ignacio Chávez. Mexico City, Mexico.
| |
Collapse
|
|
19
|
Dissociation of natriuresis and diuresis by oxytocin molecular forms in rats. PLoS One 2019; 14:e0219205. [PMID: 31269062 PMCID: PMC6608960 DOI: 10.1371/journal.pone.0219205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 06/18/2019] [Indexed: 12/20/2022] Open
Abstract
In the rat, oxytocin (OT) produces dose-dependent diuretic and natriuretic responses. Post-translational enzymatic conversion of the OT biosynthetic precursor forms both mature and C-terminally extended peptides. The plasma concentrations of these C-terminally extended peptides (OT-G; OT-GK and OT-GKR) are elevated in newborns and pregnant rats. Intravenous injection of OT-GKR to rats inhibits diuresis, whereas injection of amidated OT stimulates diuresis. Since OT and OT-GKR show different effects on the urine flow, we investigated whether OT-GKR modulates renal action by inhibition of the arginine-vasopressin (AVP) receptor V2 (V2R), the receptor involved in renal water reabsorption. Experiments were carried out in the 8-week-old Wistar rats receiving intravenous (iv) injections of vehicle, OT, OT-GKR or OT+OT-GKR combination. OT (10 μmol/kg) increased urine outflow by 40% (P<0.01) and sodium excretion by 47% (P<0.01). Treatment with OT-GKR (10 μmol/kg) decreased diuresis by 50% (P<0.001), decreased sodium excretion by 50% (P<0.05) and lowered potassium by 42% (P<0.05). OT antagonist (OTA) reduced diuresis and natriuresis exerted by OT, whereas the anti-diuretic effect of OT-GKR was unaffected by OTA. The treatment with V2R antagonist (V2A) in the presence and absence of OT induced diuresis, sodium and potassium outflow. V2A in the presence of OT-GKR only partially increased diuresis and natriuresis. Autoradiography and molecular docking analysis showed potent binding of OT-GKR to V2R. Finally, the release of cAMP from CHO cells overexpressing V2 receptor was induced by low concentration of AVP (EC50:4.2e-011), at higher concentrations of OT (EC50:3.2e-010) and by the highest concentrations of OT-GKR (EC50:1.1e-006). OT-GKR potentiated cAMP release when combined with AVP, but blocked cAMP release when combined with OT. These results suggest that OT-GKR by competing for the OT renal receptor (OTR) and binding to V2R in the kidney, induces anti-diuretic, anti-natriuretic, and anti-kaliuretic effects.
Collapse
|
|
20
|
Wang B, Sansom SC. Potassium-sparing effects of furosemide in mice on high-potassium diets. Am J Physiol Renal Physiol 2019; 316:F970-F973. [PMID: 30838871 DOI: 10.1152/ajprenal.00614.2018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In individuals on a regular "Western" diet, furosemide induces a kaliuresis and reduction in plasma K concentration by inhibiting Na reabsorption in the thick ascending limb of Henle's loop, enhancing delivery of Na to the aldosterone-sensitive distal nephron. In the aldosterone-sensitive distal nephron, the increased Na delivery stimulates K wasting due to an exaggerated exchange of epithelial Na channel-mediated Na reabsorption of secreted K. The effects of furosemide are different in mice fed a high-K, alkaline (HK) diet: the large-conductance Ca-activated K (BK) channel, in conjunction with the BK β4-subunit (BK-α/β4), mediates K secretion from intercalated cells (IC) of the connecting tubule and collecting ducts. The urinary alkaline load is necessary for BK-α/β4-mediated K secretion in HK diet-fed mice. However, furosemide acidifies the urine by increasing vacuolar ATPase expression and acid secretion from IC, thereby inhibiting BK-α/β4-mediated K secretion and sparing K. In mice fed a low-Na, high-K (LNaHK) diet, furosemide causes a greater increase in plasma K concentration and reduction in K excretion than in HK diet-fed mice. Micropuncture of the early distal tubule of mice fed a LNaHK diet, but not a regular or a HK diet, reveals K secretion in the thick ascending limb of Henle's loop. The sites of action of K secretion in individuals consuming a high-K diet should be taken into account when diuretic agents known to waste K with low or moderate K intakes are prescribed.
Collapse
Affiliation(s)
- Bangchen Wang
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center , Omaha, Nebraska
| | - Steven C Sansom
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center , Omaha, Nebraska
| |
Collapse
|
|
21
|
Gatineau E, Cohn DM, Poglitsch M, Loria AS, Gong M, Yiannikouris F. Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system. Am J Physiol Heart Circ Physiol 2019; 316:H506-H515. [PMID: 30550352 PMCID: PMC6734055 DOI: 10.1152/ajpheart.00473.2018] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 12/30/2022]
Abstract
Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.
Collapse
Affiliation(s)
- Eva Gatineau
- Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky
| | - Dianne M Cohn
- Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky
| | | | - Analia S Loria
- Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky
| | - Ming Gong
- Department of Physiology, University of Kentucky , Lexington, Kentucky
| | - Frédérique Yiannikouris
- Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky
| |
Collapse
|
|
22
|
Abstract
Tolvaptan (TLV) is a diuretic agent administrated for heart failure (HF) only in Japan. Many clinical findings have been obtained from the accumulation of clinical experience, and the administration of TLV reportedly avoids causing a reduction in the renal function. In addition, TLV has been reported to exert effects other than diuresis. The early start of TLV after hospitalization shortens the length of the hospital stay, and continuous TLV after discharge extends the period until re-hospitalization of HF patients. TLV is thought to function via vasopressin V2 receptor antagonism. However, no significant differences in the long-term prognosis were noted between the group using TLV and not using TLV in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trial, and effects other than diuresis are not useful for all HF patients. Therefore, it is necessary to identify patients who may experience effects other than diuresis with TLV administration. The accumulation of more patients and findings from further large-scale clinical trials will be necessary in order to clarify these points.
Collapse
Affiliation(s)
- Shunsuke Kiuchi
- Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Japan
| | - Takanori Ikeda
- Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Japan
| |
Collapse
|
|
23
|
Correlation between Urinary Excretion of Arginine-Vasopressin and Renal Reabsorption of Sodium and Water. Bull Exp Biol Med 2019; 166:417-420. [DOI: 10.1007/s10517-019-04363-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Indexed: 11/25/2022]
|
|
24
|
Rud C, Pedersen AKN, Wilkens TL, Borre M, Andersen JR, Moeller HB, Dahlerup JF, Hvas CL. An iso-osmolar oral supplement increases natriuresis and does not increase stomal output in patients with an ileostomy: A randomised, double-blinded, active comparator, crossover intervention study. Clin Nutr 2018; 38:2079-2086. [PMID: 30396772 DOI: 10.1016/j.clnu.2018.10.014] [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: 04/05/2018] [Revised: 09/20/2018] [Accepted: 10/17/2018] [Indexed: 11/15/2022]
Abstract
BACKGROUND Patients with an ileostomy often experience fluid and electrolyte depletion because of gastrointestinal loss. This study aimed to compare how an iso-osmolar and a hyperosmolar oral supplement affect ileostomy output, urine production, and natriuresis as proxy measurements of water-electrolyte balance. METHODS In a randomised, double-blinded, active comparator, crossover intervention study, we included eight adult ileostomy patients who were independent of parenteral support. We investigated how an iso-osmolar (279 mOsm/kg) and a hyperosmolar (681 mOsm/kg) oral supplement affected ileostomy output mass, urine volume, and natriuresis. In addition to their habitual diet, each participant ingested 800 mL/day of either the iso-osmolar or hyperosmolar supplement in each of two study periods. Each period started with 24-hour baseline measurements, and the supplements were ingested during the following 48 h. All measurements were repeated in the last 24 h. RESULTS No statistically significant changes in ileostomy output were detected following the intake of either oral supplement (median (range) 67 (-728 to 290) g/day, p = 0.25) despite increased fluid intake. Compared with the hyperosmolar supplement, the iso-osmolar supplement induced a statistically significant increase in urine volume (470 (0-780) mL/day, p = 0.02) and natriuresis (36 (0-66) mmol/day, p = 0.02). CONCLUSION Intake of the two oral supplements did not affect ileostomy output during this short intervention. Natriuresis increased following intake of the iso-osmolar supplement compared to that after ingesting the hyperosmolar supplement, indicating that patients with an ileostomy may benefit from increasing their ingestion of iso-osmolar fluids. ClinicalTrials.gov identifier:NCT03348709.
Collapse
Affiliation(s)
- Charlotte Rud
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8200, Denmark; Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-1958, Denmark.
| | - Anne Kathrine Nissen Pedersen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8200, Denmark; Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-1958, Denmark; Department of Biomedicine, Aarhus University, DK-8000, Denmark.
| | - Trine Levring Wilkens
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8200, Denmark; Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-1958, Denmark.
| | - Mette Borre
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8200, Denmark.
| | - Jens Rikardt Andersen
- Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-1958, Denmark.
| | - Hanne B Moeller
- Department of Biomedicine, Aarhus University, DK-8000, Denmark.
| | - Jens Frederik Dahlerup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8200, Denmark.
| | - Christian Lodberg Hvas
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8200, Denmark.
| |
Collapse
|
|
25
|
Comparison of the effects of tolvaptan and furosemide on renal water and sodium excretion in patients with heart failure and advanced chronic kidney disease: a subanalysis of the K-STAR study. Clin Exp Nephrol 2018; 22:1395-1403. [PMID: 29934667 DOI: 10.1007/s10157-018-1603-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 06/12/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND Tolvaptan (TLV) is known to increase electrolyte-free water clearance. However, TLV actions on renal electrolytes including urine sodium (uNa) excretion and its consequences are less well understood. This subanalysis investigated the effect of add-on TLV compared to increased furosemide (FUR) on both electrolyte-free water and electrolyte clearance in patients with congestive heart failure (CHF) complicated by advanced chronic kidney disease (CKD). METHODS The Kanagawa Aquaresis Investigators Trial of TLV on HF Patients with Renal Impairment (K-STAR) was a multicenter, open-labeled, randomized, and controlled prospective clinical study. Eighty-one Japanese patients with CHF and residual signs of congestion despite oral FUR treatment (≥ 40 mg/day) were recruited and randomly assigned to a 7-day add-on treatment with either ≤ 40 mg/day FUR or ≤ 15 mg/day TLV. Electrolyte-free water clearance, electrolyte osmolar clearance and electrolyte excretion were compared between the two groups before and after therapy. RESULTS The change (Δ) in electrolyte-free water clearance was significantly higher in the add-on TLV group than in the add-on FUR group. However, Δelectrolyte osmolar clearance was also higher in the add-on TLV group than in the increased FUR group. This was primarily because ΔuNa excretion was significantly higher in the add-on TLV group than in the increased FUR group, since Δurine potassium excretion was significantly lower in the add-on TLV group than in the increased FUR group. CONCLUSIONS Add-on TLV may increase both renal water and Na excretion in CHF patients with advanced CKD to a greater degree than increased FUR.
Collapse
|
|
26
|
Gaur P, Saini S, Vats P, Kumar B. Regulation, signalling and functions of hormonal peptides in pulmonary vascular remodelling during hypoxia. Endocrine 2018; 59:466-480. [PMID: 29383676 DOI: 10.1007/s12020-018-1529-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 01/10/2018] [Indexed: 01/06/2023]
Abstract
Hypoxic state affects organism primarily by decreasing the amount of oxygen reaching the cells and tissues. To adjust with changing environment organism undergoes mechanisms which are necessary for acclimatization to hypoxic stress. Pulmonary vascular remodelling is one such mechanism controlled by hormonal peptides present in blood circulation for acclimatization. Activation of peptides regulates constriction and relaxation of blood vessels of pulmonary and systemic circulation. Thus, understanding of vascular tone maintenance and hypoxic pulmonary vasoconstriction like pathophysiological condition during hypoxia is of prime importance. Endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and renin angiotensin system (RAS) function, their receptor functioning and signalling during hypoxia in different body parts point them as disease markers. In vivo and in vitro studies have helped understanding the mechanism of hormonal peptides for better acclimatization to hypoxic stress and interventions for better management of vascular remodelling in different models like cell, rat, and human is discussed in this review.
Collapse
Affiliation(s)
- Priya Gaur
- Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India
| | - Supriya Saini
- Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India
| | - Praveen Vats
- Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India.
| | - Bhuvnesh Kumar
- Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India
| |
Collapse
|
|
27
|
Jiang H, Li J, Yu K, Yang H, Min X, Chen H, Wu T. Associations of estimated glomerular filtration rate and blood urea nitrogen with incident coronary heart disease: the Dongfeng-Tongji Cohort Study. Sci Rep 2017; 7:9987. [PMID: 28855533 PMCID: PMC5577187 DOI: 10.1038/s41598-017-09591-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 07/21/2017] [Indexed: 01/09/2023] Open
Abstract
Estimated glomerular filtration rate (eGFR) has been reported to be associated with risk of incident coronary heart disease (CHD), and blood urea nitrogen (BUN) has been shown to be a strong predictor of mortality in patients with heart failure (HF). However, such epidemiological evidence from Chinese population was still limited. We used Cox proportional-hazards regression models to investigate the associations of eGFR and BUN with risk of incident CHD in the prospective Dongfeng-Tongji (DFTJ) cohort. After fully adjusted for potential confounders, a 10-unit decline in eGFR was associated with higher risk for CHD (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.01-1.09); compared with individuals with normal eGFR levels (eGFR ≥ 90 ml/min per 1.73 m2), individuals with a mild-to-severe eGFR decline (15 to 60 ml/min per 1.73 m2) were at significantly greater risk for CHD (HR 1.25, 95% CI 1.05-1.48; P = 0.011). Compared with individuals in the lowest tertile of BUN, those in the highest tertile were at significantly greater risk for CHD (HR 1.17, 95% CI 1.03-1.33; P = 0.014). In conclusion, a mild-to-severe decline in eGFR or a raised level of BUN might be associated with increased risk of incident CHD in middle-aged and elderly Chinese populations.
Collapse
Affiliation(s)
- Haijing Jiang
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Li
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kuai Yu
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Handong Yang
- Dongfeng Central Hospital, Dongfeng Motor Corporation and Hubei University of Medicine, Shiyan, China
| | - Xinwen Min
- Dongfeng Central Hospital, Dongfeng Motor Corporation and Hubei University of Medicine, Shiyan, China
| | - Huanqian Chen
- Dongfeng Central Hospital, Dongfeng Motor Corporation and Hubei University of Medicine, Shiyan, China
| | - Tangchun Wu
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
28
|
Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model. Infect Immun 2017; 85:IAI.00264-17. [PMID: 28438974 DOI: 10.1128/iai.00264-17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/13/2017] [Indexed: 11/20/2022] Open
Abstract
Bacillus anthracis edema toxin (ET) consists of protective antigen (PA), necessary for host cell toxin uptake, and edema factor (EF), the toxic moiety which increases host cell cyclic AMP (cAMP). Since vasopressin stimulates renal water and sodium reabsorption via increased tubular cell cAMP levels, we hypothesized the ET would also do so. To test this hypothesis, we employed an isolated perfused rat kidney model. Kidneys were isolated and perfused with modified Krebs-Henseleit buffer. Perfusate and urine samples were obtained at baseline and every 10 min over 150 min following the addition of challenges with or without treatments to the perfusate. In kidneys perfused under constant flow or constant pressure, compared to PA challenge (n = 14 or 15 kidneys, respectively), ET (13 or 15 kidneys, respectively) progressively increased urine cAMP levels, water and sodium reabsorption, and urine osmolality and decreased urine output (P ≤ 0.04, except for sodium reabsorption under constant pressure [P = 0.17]). In ET-challenged kidneys, compared to placebo treatment, adefovir, an EF inhibitor, decreased urine cAMP levels, water and sodium reabsorption, and urine osmolality and increased urine output, while raxibacumab, a PA-directed monoclonal antibody (MAb), decreased urine cAMP levels, free water reabsorption, and urine osmolality and increased urine output (P ≤ 0.03 except for urine output with raxibacumab [P = 0.17]). Upon immunohistochemistry, aquaporin 2 was concentrated along the apical membrane of tubular cells with ET but not PA, and urine aquaporin 2 levels were higher with ET (5.52 ± 1.06 ng/ml versus 1.51 ± 0.44 ng/ml [means ± standard errors of the means {SEM}; P = 0.0001). Edema toxin has renal effects that could contribute to extravascular fluid collection characterizing anthrax infection clinically.
Collapse
|
|
29
|
Antonio LS, Jeggle P, MacVinish LJ, Bartram JC, Miller H, Jarvis GE, Levy FM, Santesso MR, Leite AL, Oliveira RC, Buzalaf MAR, Edwardson JM. The effect of fluoride on the structure, function, and proteome of a renal epithelial cell monolayer. ENVIRONMENTAL TOXICOLOGY 2017; 32:1455-1467. [PMID: 27548804 DOI: 10.1002/tox.22338] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 08/08/2016] [Accepted: 08/08/2016] [Indexed: 06/06/2023]
Abstract
High concentrations of fluoride in the body may cause toxic effects. Here, we investigated the effects of fluoride on the structure, function, and proteome of a cortical collecting duct epithelium in vitro. Kidney tubule cells (M-1) were chosen because the concentration of fluoride in the kidney is 4-5-fold higher than that in plasma. Mouse M-1 cell monolayers were incubated in fluoride-containing media, and the amiloride-sensitive short-circuit current and transepithelial resistance were measured. The Young's modulus of the epithelium was determined using atomic force microscopy, and the effect of fluoride on epithelial structure was assessed using scanning and transmission electron microscopy, and immunofluorescence. Differences in the expression of membrane proteins were evaluated using proteomics and bioinformatics. Fluoride exposure reduced both transepithelial Na+ transport and resistance. The IC50 for fluoride was ∼300 µM for both effects, and the half-times for the decays of ion transport and resistance were 8.4 h and 3.6 days, respectively. Fluoride treatment did not affect the sensitivity of Na+ transport to amiloride. The Young's modulus of the epithelium was also unaffected by fluoride; however, the functional effects of fluoride were accompanied by marked structural effects. Proteomic analysis revealed changes in expression of a number of proteins, and particularly mitochondrial proteins. Treatment with fluoride had profound effects on the structure, function and proteome of a model cortical collecting duct epithelium. Significantly, however, these effects were produced only at concentrations considerably higher than those likely to be encountered in vivo. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1455-1467, 2017.
Collapse
Affiliation(s)
- Ligia S Antonio
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Pia Jeggle
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Lesley J MacVinish
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - James C Bartram
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Henry Miller
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Gavin E Jarvis
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Flávia M Levy
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
| | - Mariana R Santesso
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
| | - Aline L Leite
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
| | - Rodrigo C Oliveira
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
| | - Marília A R Buzalaf
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
| | - J Michael Edwardson
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
30
|
Uojima H, Kinbara T, Hidaka H, Sung JH, Ichida M, Tokoro S, Masuda S, Takizawa S, Sasaki A, Koizumi K, Egashira H, Kako M. Close correlation between urinary sodium excretion and response to tolvaptan in liver cirrhosis patients with ascites. Hepatol Res 2017; 47:E14-E21. [PMID: 27059410 DOI: 10.1111/hepr.12716] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 03/18/2016] [Accepted: 03/29/2016] [Indexed: 02/08/2023]
Abstract
AIM To assess the correlation between response to tolvaptan and treatment-related factors in liver cirrhosis patients. METHODS This single-center retrospective study was carried out at Shonan Kamakura General Hospital in Kanagawa, Japan, between October 2013 and September 2015. Forty-three liver cirrhosis patients (mean age, 65.7 years) with insufficient responses to conventional diuretics for at least 7 days were enrolled. All patients received oral tolvaptan (7.5 mg/day for 7 days) and guideline-directed medical therapy including sodium intake restrictions. A responder to tolvaptan was defined as a patient having a ≥2-kg decrease in body weight 1 week after commencing drug treatment, and a non-responder was defined as a patient not losing ≥2 kg in body weight 1 week after commencing treatment. We investigated the correlation of change in body weight for 1 week after drug administration compared to baseline clinical characteristics. RESULTS The mean body weight change from the baseline on the final dosing day was -2.47 ± 3.34 kg (P < 0.0001). There were 20 (46.5%) responders to tolvaptan. Urinary sodium and volume excretion was higher in responders than in non-responders (108.2 ± 70.5 vs 42.6 ± 36.7, P = 0.0003; 1462.8 ± 625.7 vs 960.9 ± 600.6, P = 0.0073). Logistic regression analyses for responders to tolvaptan were carried out, and independent correlation of the responders was urinary sodium excretion (P = 0.0114; hazard ratio, 0.9418; 95% confidence interval, 0.8768-0.9896) in the multivariate analyses. CONCLUSION In decompensated liver cirrhosis patients, urinary excretion sodium showed good correlation with tolvaptan response.
Collapse
Affiliation(s)
- Haruki Uojima
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan.,Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Kinbara
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ji Hyun Sung
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Masachika Ichida
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Shinnosuke Tokoro
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Sakue Masuda
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Satoshi Takizawa
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Akiko Sasaki
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Kazuya Koizumi
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Hideto Egashira
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Makoto Kako
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| |
Collapse
|
|
31
|
Qian J, Mummalaneni S, Phan THT, Heck GL, DeSimone JA, West D, Mahavadi S, Hojati D, Murthy KS, Rhyu MR, Spielman AI, Özdener MH, Lyall V. Cyclic-AMP regulates postnatal development of neural and behavioral responses to NaCl in rats. PLoS One 2017; 12:e0171335. [PMID: 28192441 PMCID: PMC5305205 DOI: 10.1371/journal.pone.0171335] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Accepted: 01/18/2017] [Indexed: 02/07/2023] Open
Abstract
During postnatal development rats demonstrate an age-dependent increase in NaCl chorda tympani (CT) responses and the number of functional apical amiloride-sensitive epithelial Na+ channels (ENaCs) in salt sensing fungiform (FF) taste receptor cells (TRCs). Currently, the intracellular signals that regulate the postnatal development of salt taste have not been identified. We investigated the effect of cAMP, a downstream signal for arginine vasopressin (AVP) action, on the postnatal development of NaCl responses in 19-23 day old rats. ENaC-dependent NaCl CT responses were monitored after lingual application of 8-chlorophenylthio-cAMP (8-CPT-cAMP) under open-circuit conditions and under ±60 mV lingual voltage clamp. Behavioral responses were tested using 2 bottle/24h NaCl preference tests. The effect of [deamino-Cys1, D-Arg8]-vasopressin (dDAVP, a specific V2R agonist) was investigated on ENaC subunit trafficking in rat FF TRCs and on cAMP generation in cultured adult human FF taste cells (HBO cells). Our results show that in 19-23 day old rats, the ENaC-dependent maximum NaCl CT response was a saturating sigmoidal function of 8-CPT-cAMP concentration. 8-CPT-cAMP increased the voltage-sensitivity of the NaCl CT response and the apical Na+ response conductance. Intravenous injections of dDAVP increased ENaC expression and γ-ENaC trafficking from cytosolic compartment to the apical compartment in rat FF TRCs. In HBO cells dDAVP increased intracellular cAMP and cAMP increased trafficking of γ- and δ-ENaC from cytosolic compartment to the apical compartment 10 min post-cAMP treatment. Control 19-23 day old rats were indifferent to NaCl, but showed clear preference for appetitive NaCl concentrations after 8-CPT-cAMP treatment. Relative to adult rats, 14 day old rats demonstrated significantly less V2R antibody binding in circumvallate TRCs. We conclude that an age-dependent increase in V2R expression produces an AVP-induced incremental increase in cAMP that modulates the postnatal increase in TRC ENaC and the neural and behavioral responses to NaCl.
Collapse
Affiliation(s)
- Jie Qian
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Shobha Mummalaneni
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Tam-Hao T. Phan
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Gerard L. Heck
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - John A. DeSimone
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - David West
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Sunila Mahavadi
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Deanna Hojati
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Karnam S. Murthy
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Mee-Ra Rhyu
- Korea Food Research Institute, Bundang-gu, Sungnam-si, Gyeonggi-do, Korea
| | | | - Mehmet Hakan Özdener
- Monell Chemical Senses Center, Philadelphia, Pennsylvania, United States of America
| | - Vijay Lyall
- Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| |
Collapse
|
|
32
|
Srikan P, Callen B, Phillips K, Tavakoli A, Brockett R, Hanucharurnkul S, Beebe L. Testing a Model of Sodium Reduction in Hypertensive Older Thai Adults. J Nutr Gerontol Geriatr 2017; 36:48-62. [PMID: 28107108 DOI: 10.1080/21551197.2016.1274278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Hypertensive older adults will benefit if there is a clear understanding of the factors related to sodium reduction. That would raise awareness of the causes, consequently reducing many health risks, lowering health care costs, and diminishing economic and social burden from high blood pressure. This study explored predictors of urinary sodium excretion. A cross-sectional, correlational study was conducted in 312 hypertensive older Thai adults. Questionnaires related to knowledge, self-care agency, self-care behavior of sodium reduction, and 24-hour urinary sodium analyses were used, followed by the application of structural equation modeling and the Analysis of Moment Structures program. Self-care agency, knowledge, self-care behavior, rural/urban location, and education accounted for 61% of urinary sodium excretion. Self-care agency, knowledge, and self-care behavior were the main predictors in the urinary sodium excretion model. This study suggests establishing supportive educative sodium reduction-related programs that improve knowledge and enhance self-care agency, as well as a comparison of the changes of sodium reduction self-care behavior and urinary sodium excretion over time after the intervention.
Collapse
Affiliation(s)
| | - Bonnie Callen
- b College of Nursing , University of Tennessee , Knoxville , Tennessee , USA
| | - Kenneth Phillips
- b College of Nursing , University of Tennessee , Knoxville , Tennessee , USA
| | - Abbas Tavakoli
- c College of Nursing , University of South Carolina , Columbia , North Carolina , USA
| | - Ralph Brockett
- d College of Education , University of Tennessee , Knoxville , Tennessee , USA
| | | | - Lora Beebe
- b College of Nursing , University of Tennessee , Knoxville , Tennessee , USA
| |
Collapse
|
|
33
|
Pavlov TS, Staruschenko A. Involvement of ENaC in the development of salt-sensitive hypertension. Am J Physiol Renal Physiol 2016; 313:F135-F140. [PMID: 28003189 DOI: 10.1152/ajprenal.00427.2016] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 12/20/2016] [Accepted: 12/20/2016] [Indexed: 02/07/2023] Open
Abstract
Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral resistance. It is commonly accepted that increased renal sodium handling and plasma volume expansion are necessary factors for the development of salt-induced hypertension. The epithelial sodium channel (ENaC) is a trimeric ion channel expressed in the distal nephron that plays a critical role in the regulation of sodium reabsorption in both normal and pathological conditions. In this mini-review, we summarize recent studies investigating the role of ENaC in the development of salt-sensitive hypertension. On the basis of experimental data obtained from the Dahl salt-sensitive rats, we and others have demonstrated that abnormal ENaC activation in response to a dietary NaCl load contributes to the development of high blood pressure in this model. The role of different humoral factors, such as the components of the renin-angiotensin-aldosterone system, members of the epidermal growth factors family, arginine vasopressin, and oxidative stress mediating the effects of dietary salt on ENaC are discussed in this review to highlight future research directions and to determine potential molecular targets for drug development.
Collapse
Affiliation(s)
- Tengis S Pavlov
- Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan; and
| | | |
Collapse
|
|
34
|
Ramkumar N, Stuart D, Mironova E, Bugay V, Wang S, Abraham N, Ichihara A, Stockand JD, Kohan DE. Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport. Am J Physiol Renal Physiol 2016; 311:F186-94. [PMID: 27053687 DOI: 10.1152/ajprenal.00088.2016] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/31/2016] [Indexed: 12/31/2022] Open
Abstract
The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.
Collapse
Affiliation(s)
- Nirupama Ramkumar
- Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;
| | - Deborah Stuart
- Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah
| | - Elena Mironova
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and
| | - Vladislav Bugay
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and
| | - Shuping Wang
- Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah
| | - Nikita Abraham
- Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah
| | - Atsuhiro Ichihara
- Department of Medicine II, Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan
| | - James D Stockand
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and
| | - Donald E Kohan
- Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah; Veterans Affairs Medical Center, Salt Lake City, Utah
| |
Collapse
|
|
35
|
Kutina AV, Golosova DV, Marina AS, Shakhmatova EI, Natochin YV. Role of Vasopressin in the Regulation of Renal Sodium Excretion: Interaction with Glucagon-Like Peptide-1. J Neuroendocrinol 2016; 28. [PMID: 26791475 DOI: 10.1111/jne.12367] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 01/15/2016] [Accepted: 01/15/2016] [Indexed: 12/14/2022]
Abstract
The present study aimed to investigate the potential physiological role of vasopressin and the incretin hormone of the gastrointestinal tract (glucagon-like peptide-1; GLP-1) in the regulation of the water-salt balance in a hyperosmolar state as a result of sodium loadings. In rats, the administration of hypertonic NaCl solution resulted in a significant increase in natriuresis, which correlated with the vasopressin excretion rate. Natriuresis following an i.p. NaCl load (23.2 ± 1.4 μmol/min/kg) was enhanced by inhibition of V2 receptors (51.6 ± 3.7 μmol/min/kg, P < 0.05) and was reduced by a V1a antagonist injection (6.3 ± 1.1 μmol/min/kg, P < 0.05). Compared to i.p. salt administration, oral NaCl loading induced a significant increase in the plasma GLP-1 level within 5 min and resulted in more prominent natriuresis and a smaller increase in blood sodium concentration. It was hypothesised that the basis for the fast elimination of excess sodium following an oral NaCl load could be the involvement of GLP-1 in osmoregulation combined with vasopressin. It was demonstrated that GLP-1 mimetic exenatide (1.5 nmol/kg) produced a significant decrease in proximal reabsorption and an increase in fractional sodium excretion (from 0.15 ± 0.04% to 9 ± 1%). It was also shown that vasopressin at doses of 1-10 μg/kg and the selective V1a agonist (1 μg/kg) induced an increase in sodium fractional excretion to 10 ± 2% and 8 ± 2%, respectively. Combined administration of exenatide and V1a agonist revealed their cumulative natriuretic effect, and sodium fractional excretion increased by up to 18 ± 2%. These data suggest that GLP-1 combined with vasopressin could be involved in the regulation of sodium balance in the hyperosmolar state as a result of NaCl loading. Vasopressin regulates the reabsorption of a significant portion of filtered sodium in the distal segment of the nephron and modulates the natriuretic effect of GLP-1.
Collapse
Affiliation(s)
- A V Kutina
- Laboratory of Renal Physiology and Water-Salt Balance, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, Russia
| | - D V Golosova
- Laboratory of Renal Physiology and Water-Salt Balance, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, Russia
| | - A S Marina
- Laboratory of Renal Physiology and Water-Salt Balance, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, Russia
| | - E I Shakhmatova
- Laboratory of Renal Physiology and Water-Salt Balance, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Y V Natochin
- Laboratory of Renal Physiology and Water-Salt Balance, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint-Petersburg, Russia
| |
Collapse
|
|
36
|
The Role of Epithelial Sodium Channel ENaC and the Apical Cl-/HCO3- Exchanger Pendrin in Compensatory Salt Reabsorption in the Setting of Na-Cl Cotransporter (NCC) Inactivation. PLoS One 2016; 11:e0150918. [PMID: 26963391 PMCID: PMC4786216 DOI: 10.1371/journal.pone.0150918] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 02/18/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The absence of NCC does not cause significant salt wasting in NCC deficient mice under basal conditions. We hypothesized that ENaC and pendrin play important roles in compensatory salt absorption in the setting of NCC inactivation, and their inhibition and/or downregulation can cause significant salt wasting in NCC KO mice. METHODS WT and NCC KO mice were treated with a daily injection of either amiloride, an inhibitor of ENaC, or acetazolamide (ACTZ), a blocker of salt and bicarbonate reabsorption in the proximal tubule and an inhibitor of carbonic anhydrases in proximal tubule and intercalated cells, or a combination of acetazolamide plus amiloride for defined durations. Animals were subjected to daily balance studies. At the end of treatment, kidneys were harvested and examined. Blood samples were collected for electrolytes and acid base analysis. RESULTS Amiloride injection significantly increased the urine output (UO) in NCC KO mice (from 1.3 ml/day before to 2.5 ml/day after amiloride, p<0.03, n = 4) but caused only a slight change in UO in WT mice (p>0.05). The increase in UO in NCC KO mice was associated with a significant increase in sodium excretion (from 0.25 mmol/24 hrs at baseline to 0.35 mmol/24 hrs after amiloride injection, p<0.05, n = 4). Daily treatment with ACTZ for 6 days resulted in >80% reduction of kidney pendrin expression in both WT and NCC KO mice. However, ACTZ treatment noticeably increased urine output and salt excretion only in NCC KO mice (with urine output increasing from a baseline of 1.1 ml/day to 2.3 ml/day and sodium excretion increasing from 0.22 mmole/day before to 0.31 mmole/day after ACTZ) in NCC KO mice; both parameters were significantly higher than in WT mice. Western blot analysis demonstrated significant enhancement in ENaC expression in medulla and cortex of NCC KO and WT mice in response to ACTZ injection for 6 days, and treatment with amiloride in ACTZ-pretreated mice caused a robust increase in salt excretion in both NCC KO and WT mice. Pendrin KO mice did not display a significant increase in urine output or salt excretion after treatment with amiloride or ACTZ. CONCLUSION 1. ENaC plays an important role in salt reabsorption in NCC KO mice. 2. NCC contributes to compensatory salt reabsorption in the setting of carbonic anhydrase inhibition, which is associated with increased delivery of salt from the proximal tubule and the down regulation of pendrin. 3. ENaC is upregulated by ACTZ treatment and its inhibition by amiloride causes significant diuresis in NCC KO and WT mice. Despite being considered mild agents individually, we propose that the combination of acetazolamide and amiloride in the setting of NCC inhibition (i.e., hydrochlorothiazide) will be a powerful diuretic regimen.
Collapse
|
|
37
|
Peti-Peterdi J, Kishore BK, Pluznick JL. Regulation of Vascular and Renal Function by Metabolite Receptors. Annu Rev Physiol 2015; 78:391-414. [PMID: 26667077 DOI: 10.1146/annurev-physiol-021115-105403] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis-from salt and water balance to metabolism-by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families-(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and
Collapse
Affiliation(s)
- János Peti-Peterdi
- Department of Physiology and Biophysics and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033;
| | - Bellamkonda K Kishore
- Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah 84148;
| | - Jennifer L Pluznick
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;
| |
Collapse
|
|
38
|
Rafat C, Flamant M, Gaudry S, Vidal-Petiot E, Ricard JD, Dreyfuss D. Hyponatremia in the intensive care unit: How to avoid a Zugzwang situation? Ann Intensive Care 2015; 5:39. [PMID: 26553121 PMCID: PMC4639545 DOI: 10.1186/s13613-015-0066-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 09/02/2015] [Indexed: 12/11/2022] Open
Abstract
Hyponatremia is a common
electrolyte derangement in the setting of the intensive care unit. Life-threatening neurological complications may arise not only in case of a severe (<120 mmol/L) and acute fall of plasma sodium levels, but may also stem from overly rapid correction of hyponatremia. Additionally, even mild hyponatremia carries a poor short-term and long-term prognosis across a wide range of conditions. Its multifaceted and intricate physiopathology may seem deterring at first glance, yet a careful multi-step diagnostic approach may easily unravel the underlying mechanisms and enable physicians to adopt the adequate measures at the patient’s bedside. Unless hyponatremia is associated with obvious extracellular fluid volume increase such as in heart failure or cirrhosis, hypertonic saline therapy is the cornerstone of the therapeutic of profound or severely symptomatic hyponatremia. When overcorrection of hyponatremia occurs, recent data indicate that re-lowering of plasma sodium levels through the infusion of hypotonic fluids and the cautious use of desmopressin acetate represent a reasonable strategy. New therapeutic options have recently emerged, foremost among these being vaptans, but their use in the setting of the intensive care unit remains to be clarified.
Collapse
Affiliation(s)
- Cédric Rafat
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,AP-HP, Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris, France.
| | - Martin Flamant
- AP-HP, Service de Physiologie Rénale, Hôpital Bichat, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Stéphane Gaudry
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,ECEVE UMR 1123, ECEVE, Paris, France.
| | - Emmanuelle Vidal-Petiot
- AP-HP, Service de Physiologie Rénale, Hôpital Bichat, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Jean-Damien Ricard
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM UMR 1137, IAME, Paris, France.
| | - Didier Dreyfuss
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM UMR 1137, IAME, Paris, France.
| |
Collapse
|
|
39
|
Blount MA, Cipriani P, Redd SK, Ordas RJ, Black LN, Gumina DL, Hoban CA, Klein JD, Sands JM. Activation of protein kinase Cα increases phosphorylation of the UT-A1 urea transporter at serine 494 in the inner medullary collecting duct. Am J Physiol Cell Physiol 2015; 309:C608-15. [PMID: 26333598 PMCID: PMC4628937 DOI: 10.1152/ajpcell.00171.2014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 08/18/2015] [Indexed: 01/20/2023]
Abstract
Hypertonicity increases urea transport, as well as the phosphorylation and membrane accumulation of UT-A1, the transporter responsible for urea permeability in the inner medullary collect duct (IMCD). Hypertonicity stimulates urea transport through PKC-mediated phosphorylation. To determine whether PKC phosphorylates UT-A1, eight potential PKC phosphorylation sites were individually replaced with alanine and subsequently transfected into LLC-PK1 cells. Of the single mutants, only ablation of the S494 site dampened induction of total UT-A1 phosphorylation by the PKC activator phorbol dibutyrate (PDBu). This result was confirmed using a newly generated antibody that specifically detected phosphorylation of UT-A1 at S494. Hypertonicity increased UT-A1 phosphorylation at S494. In contrast, activators of cAMP pathways (PKA and Epac) did not increase UT-A1 phosphorylation at S494. Activation of both PKC and PKA pathways increased plasma membrane accumulation of UT-A1, although activation of PKC alone did not do so. However, ablating the PKC site S494 decreased UT-A1 abundance in the plasma membrane. This suggests that the cAMP pathway promotes UT-A1 trafficking to the apical membrane where the PKC pathway can phosphorylate the transporter, resulting in increased UT-A1 retention at the apical membrane. In summary, activation of PKC increases the phosphorylation of UT-A1 at a specific residue, S494. Although there is no cross talk with the cAMP-signaling pathway, phosphorylation of S494 through PKC may enhance vasopressin-stimulated urea permeability by retaining UT-A1 in the plasma membrane.
Collapse
Affiliation(s)
- Mitsi A Blount
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia
| | - Penelope Cipriani
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
| | - Sara K Redd
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
| | - Ronald J Ordas
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
| | - Lauren N Black
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
| | - Diane L Gumina
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
| | - Carol A Hoban
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
| | - Janet D Klein
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia
| | - Jeff M Sands
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia
| |
Collapse
|
|
40
|
A Systems Level Analysis of Vasopressin-mediated Signaling Networks in Kidney Distal Convoluted Tubule Cells. Sci Rep 2015; 5:12829. [PMID: 26239621 PMCID: PMC4523861 DOI: 10.1038/srep12829] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 07/10/2015] [Indexed: 01/06/2023] Open
Abstract
The kidney distal convoluted tubule (DCT) plays an essential role in maintaining body sodium balance and blood pressure. The major sodium reabsorption pathway in the DCT is the thiazide-sensitive NaCl cotransporter (NCC), whose functions can be modulated by the hormone vasopressin (VP) acting via uncharacterized signaling cascades. Here we use a systems biology approach centered on stable isotope labeling by amino acids in cell culture (SILAC) based quantitative phosphoproteomics of cultured mouse DCT cells to map global changes in protein phosphorylation upon acute treatment with a VP type II receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP). 6330 unique proteins, containing 12333 different phosphorylation sites were identified. 185 sites were altered in abundance following dDAVP. Basophilic motifs were preferential targets for upregulated sites upon dDAVP stimulation, whereas proline-directed motifs were prominent for downregulated sites. Kinase prediction indicated that dDAVP increased AGC and CAMK kinase families’ activities and decreased activity of CDK and MAPK families. Network analysis implicated phosphatidylinositol-4,5-bisphosphate 3-kinase or CAMKK dependent pathways in VP-mediated signaling; pharmacological inhibition of which significantly reduced dDAVP induced increases in phosphorylated NCC at an activating site. In conclusion, this study identifies unique VP signaling cascades in DCT cells that may be important for regulating blood pressure.
Collapse
|
|
41
|
Jensen JM, Mose FH, Kulik AEO, Bech JN, Fenton RA, Pedersen EB. Changes in urinary excretion of water and sodium transporters during amiloride and bendroflumethiazide treatment. World J Nephrol 2015; 4:423-437. [PMID: 26167467 PMCID: PMC4491934 DOI: 10.5527/wjn.v4.i3.423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 03/08/2015] [Accepted: 04/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To quantify changes in urinary excretion of aquaporin2 water channels (u-AQP2), the sodium-potassium-chloride co-transporter (u-NKCC2) and the epithelial sodium channels (u-ENaC) during treatment with bendroflumethiazide (BFTZ), amiloride and placebo.
METHODS: In a randomized, double-blinded, placebo-controlled, 3-way crossover study we examined 23 healthy subjects on a standardized diet and fluid intake. The subjects were treated with amiloride 5 mg, BFTZ 1.25 mg or placebo twice a day for 4.5 d before each examination day. On the examination day, glomerular filtration rate was measured by the constant infusion clearance technique with 51Cr-EDTA as reference substance. To estimate the changes in water transport via AQP2 and sodium transport via NKCC2 and ENaC, u-NKCC2, the gamma fraction of ENaC (u-ENaCγ), and u-AQP2 were measured at baseline and after infusion with 3% hypertonic saline. U-NKCC2, u-ENaCγ, u-AQP2 and plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensin II (p-ANG II) and aldosterone (p-Aldo) were measured, by radioimmunoassay. Central blood pressure was estimated by applanation tonometry and body fluid volumes were estimated by bio-impedance spectroscopy. General linear model with repeated measures or related samples Friedman’s two-way analysis was used to compare differences. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group.
RESULTS: At baseline there were no differences in u-NKCC2, u-ENaCγ and u-AQP2. PRC, p-Ang II and p-Aldo were increased during active treatments (P < 0.001). After hypertonic saline, u-NKCC2 increased during amiloride (6% ± 34%; P = 0.081) and increased significantly during placebo (17% ± 24%; P = 0.010). U-AQP2 increased significantly during amiloride (31% ± 22%; P < 0.001) and placebo (34% ± 27%; P < 0.001), while u-NKCC2 and u-AQP2 did not change significantly during BFTZ (-7% ± 28%; P = 0.257 and 5% ± 16%; P = 0.261). U- ENaCγ increased in all three groups (P < 0.050). PRC, AngII and p-Aldo decreased to the same extent, while AVP increased, but to a smaller degree during BFTZ (P = 0.048). cDBP decreased significantly during BFTZ (P < 0.001), but not during amiloride or placebo. There were no significant differences in body fluid volumes.
CONCLUSION: After hypertonic saline, u-NKCC2 and u-AQP2 increased during amiloride, but not during BFTZ. Lower p-AVP during BFTZ potentially caused less stimulation of NKCC2 and AQP2 and subsequent lower reabsorption of water and sodium.
Collapse
|
|
42
|
Kishore BK, Carlson NG, Ecelbarger CM, Kohan DE, Müller CE, Nelson RD, Peti-Peterdi J, Zhang Y. Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus. Acta Physiol (Oxf) 2015; 214:176-88. [PMID: 25877068 PMCID: PMC4430398 DOI: 10.1111/apha.12507] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 04/08/2015] [Indexed: 12/26/2022]
Abstract
Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix(®)) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action.
Collapse
Affiliation(s)
- B. K. Kishore
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Nephrology Research, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA
- Center on Aging, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | - N. G. Carlson
- Center on Aging, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Department of Neurobiology and Anatomy, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA
| | - C. M. Ecelbarger
- Department of Medicine, Georgetown University, Washington, District of Columbia, USA
- Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, District of Columbia, USA
| | - D. E. Kohan
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Nephrology Research, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA
| | - C. E. Müller
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
| | - R. D. Nelson
- Department of Paediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | - J. Peti-Peterdi
- Department of Physiology and Biophysics, and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA
| | - Y. Zhang
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Nephrology Research, Department of Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA
| |
Collapse
|
|
43
|
Mironova E, Chen Y, Pao AC, Roos KP, Kohan DE, Bugaj V, Stockand JD. Activation of ENaC by AVP contributes to the urinary concentrating mechanism and dilution of plasma. Am J Physiol Renal Physiol 2015; 308:F237-43. [PMID: 25391898 PMCID: PMC4596725 DOI: 10.1152/ajprenal.00246.2014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 11/06/2014] [Indexed: 12/11/2022] Open
Abstract
Arginine vasopressin (AVP) activates the epithelial Na(+) channel (ENaC). The physiological significance of this activation is unknown. The present study tested if activation of ENaC contributes to AVP-sensitive urinary concentration. Consumption of a 3% NaCl solution induced hypernatremia and plasma hypertonicity in mice. Plasma AVP concentration and urine osmolality increased in hypernatremic mice in an attempt to compensate for increases in plasma tonicity. ENaC activity was elevated in mice that consumed 3% NaCl solution compared with mice that consumed a diet enriched in Na(+) with ad libitum tap water; the latter diet does not cause hypernatremia. To determine whether the increase in ENaC activity in mice that consumed 3% NaCl solution served to compensate for hypernatremia, mice were treated with the ENaC inhibitor benzamil. Coadministration of benzamil with 3% NaCl solution decreased urinary osmolality and increased urine flow so that urinary Na(+) excretion increased with no effect on urinary Na(+) concentration. This decrease in urinary concentration further increased plasma Na(+) concentration, osmolality, and AVP concentration in these already hypernatremic mice. Benzamil similarly compromised urinary concentration in water-deprived mice and in mice treated with desmopressin. These results demonstrate that stimulation of ENaC by AVP plays a critical role in water homeostasis by facilitating urinary concentration, which can compensate for hypernatremia or exacerbate hyponatremia. The present findings are consistent with ENaC in addition to serving as a final effector of the renin-angiotensin-aldosterone system and blood pressure homeostasis, also playing a key role in water homeostasis by regulating urine concentration and dilution of plasma.
Collapse
Affiliation(s)
- Elena Mironova
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas
| | - Yu Chen
- Department of Medicine, Stanford University School of Medicine, and Veterans Affairs Palo Alto Health Care System, Palo Alto, California; and
| | - Alan C Pao
- Department of Medicine, Stanford University School of Medicine, and Veterans Affairs Palo Alto Health Care System, Palo Alto, California; and
| | - Karl P Roos
- Division of Nephrology, University of Utah Health Science Center, Salt Lake City, Utah
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health Science Center, Salt Lake City, Utah
| | - Vladislav Bugaj
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas
| | - James D Stockand
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas;
| |
Collapse
|
|
44
|
Hunter RW, Craigie E, Homer NZM, Mullins JJ, Bailey MA. Acute inhibition of NCC does not activate distal electrogenic Na+ reabsorption or kaliuresis. Am J Physiol Renal Physiol 2014; 306:F457-67. [PMID: 24402096 PMCID: PMC3920023 DOI: 10.1152/ajprenal.00339.2013] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Na(+) reabsorption from the distal renal tubule involves electroneutral and electrogenic pathways, with the latter promoting K(+) excretion. The relative activities of these two pathways are tightly controlled, participating in the minute-to-minute regulation of systemic K(+) balance. The pathways are interdependent: the activity of the NaCl cotransporter (NCC) in the distal convoluted tubule influences the activity of the epithelial Na(+) channel (ENaC) downstream. This effect might be mediated by changes in distal Na(+) delivery per se or by molecular and structural adaptations in the connecting tubule and collecting ducts. We hypothesized that acute inhibition of NCC activity would cause an immediate increase in Na(+) flux through ENaC, with a concomitant increase in renal K(+) excretion. We tested this using renal clearance methodology in anesthetized mice, by the administration of hydrochlorothiazide (HCTZ) and/or benzamil (BZM) to exert specific blockade of NCC and ENaC, respectively. Bolus HCTZ elicited a natriuresis that was sustained for up to 110 min; urinary K(+) excretion was not affected. Furthermore, the magnitude of the natriuresis was no greater during concomitant BZM administration. This suggests that ENaC-mediated Na(+) reabsorption was not normally limited by Na(+) delivery, accounting for the absence of thiazide-induced kaliuresis. After dietary Na(+) restriction, HCTZ elicited a kaliuresis, but the natiuretic effect of HCTZ was not enhanced by BZM. Our findings support a model in which inhibition of NCC activity does not increase Na(+) reabsorption through ENaC solely by increasing distal Na(+) delivery but rather by inducing a molecular and structural adaptation in downstream nephron segments.
Collapse
Affiliation(s)
- Robert W Hunter
- Univ. of Edinburgh/BHF Centre for Cardiovascular Science, Rm. W3.33B, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
| | | | | | | | | |
Collapse
|
|
45
|
Abstract
The endocrine system plays a major role in human survival. Endocrine glands secrete chemical messengers or hormones that affect every tissue of the body, including the periodontium, during the life of the individual. As the endocrine system influences a broad assortment of biological activities necessary for life, a general understanding of the principal components and functions of this system is essential. A fundamental assessment of hormone structure, mechanism of action and hormone transport, as well as influence on homeostasis is reviewed. A concise evaluation of the functions of the central endocrine glands, the functions of the major peripheral endocrine glands (other than gonadal tissues) and the known relationships of these hormones to the periodontium is examined.
Collapse
|
|
46
|
Stockand JD, Vallon V, Ortiz P. In vivo and ex vivo analysis of tubule function. Compr Physiol 2013; 2:2495-525. [PMID: 23720256 DOI: 10.1002/cphy.c100051] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Analysis of tubule function with in vivo and ex vivo approaches has been instrumental in revealing renal physiology. This work allows assignment of functional significance to known gene products expressed along the nephron, primary of which are proteins involved in electrolyte transport and regulation of these transporters. Not only we have learned much about the key roles played by these transport proteins and their proper regulation in normal physiology but also the combination of contemporary molecular biology and molecular genetics with in vivo and ex vivo analysis opened a new era of discovery informative about the root causes of many renal diseases. The power of in vivo and ex vivo analysis of tubule function is that it preserves the native setting and control of the tubule and proteins within tubule cells enabling them to be investigated in a "real-life" environment with a high degree of precision. In vivo and ex vivo analysis of tubule function continues to provide a powerful experimental outlet for testing, evaluating, and understanding physiology in the context of the novel information provided by sequencing of the human genome and contemporary genetic screening. These tools will continue to be a mainstay in renal laboratories as this discovery process continues and as we continue to identify new gene products functionally compromised in renal disease.
Collapse
Affiliation(s)
- James D Stockand
- Department of Physiology, University of Texas Health Science Center, San Antonio, Texas, USA.
| | | | | |
Collapse
|
|
47
|
Murahata Y, Yamamoto A, Miki Y, Hikasa Y. Antagonistic effects of atipamezole, yohimbine and prazosin on medetomidine-induced diuresis in healthy cats. J Vet Med Sci 2013; 76:173-82. [PMID: 24107430 PMCID: PMC3982822 DOI: 10.1292/jvms.13-0398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine and prazosin on medetomidine-induced diuresis in healthy cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 40 µg/kg medetomidine intramuscularly and saline (as the control), 160 µg/kg prazosin, or 40, 160 or 480 µg/kg atipamezole or yohimbine intravenously 0.5 hr later. Volume, pH and specific gravity of urine; plasma arginine vasopressin (AVP) level; and creatinine, osmolality and electrolyte levels in both urine and plasma were measured. Both atipamezole and yohimbine, but not prazosin, antagonized medetomidine-induced diuresis. The antidiuretic effect of atipamezole was more potent than that of yohimbine, but was not dose dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed medetomidine-induced decreases in both urine specific gravity and osmolality and increases in plasma osmolality and free-water clearance. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP level, although the highest dose of both atipamezole and yohimbine initially and temporarily increased plasma AVP levels, suggesting that this may partly influence the antidiuretic effects of both agents. The diuretic effect of medetomidine in cats may be mediated by α2-adrenoceptors, but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against medetomidine-induced diuresis in healthy cats.
Collapse
Affiliation(s)
- Yusuke Murahata
- Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
| | | | | | | |
Collapse
|
|
48
|
Jensen JM, Mose FH, Bech JN, Nielsen S, Pedersen EB. Effect of volume expansion with hypertonic- and isotonic saline and isotonic glucose on sodium and water transport in the principal cells in the kidney. BMC Nephrol 2013; 14:202. [PMID: 24067081 PMCID: PMC3849534 DOI: 10.1186/1471-2369-14-202] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 09/23/2013] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The renal distal nephron plays an important role in the maintenance of sodium balance, extra cellular volume and blood pressure. The degree of water transport, via aquaporin2 water channels (AQP2), and sodium transport, via epithelial sodium channels (ENaC) in renal collecting duct principal cells are reflected by the level of urinary excretion of AQP2 (u-AQP2) and the γ-fraction of ENaC (u-ENaCγ). The effects of an acute intravenous volume load with isotonic saline, hypertonic saline and glucose on u-AQP2, u-ENaCγ and underlying mechanisms have never been studied in a randomized, placebo-controlled trial in healthy humans. METHODS We studied the effects of 0.9% saline (23 ml/kg), 3% saline (7 ml/kg) and 5% glucose (23 ml/kg) on u-AQP2 and u-ENaCγ, fractional sodium excretion (FENa), free water clearance (CH2O), and plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (ANG II) and aldosterone (Aldo) in a randomized, crossover study of 23 healthy subjects, who consumed a standardized diet, regarding calories, sodium and fluid for 4 days before each examination day. RESULTS After isotonic saline infusion, u-AQP2 increased (27%). CH2O and u-ENaCγ were unchanged, whereas FENa increased (123%). After hypertonic saline infusion, there was an increase in u-AQP2 (25%), u-ENaCγ (19%) and FENa (96%), whereas CH2O decreased (-153%). After isotonic glucose infusion, there was a decrease in u-AQP2 (-16%), ENaCγ (-10%) and FENa (-44%) whereas CH2O increased (164%). AVP remained unchanged after isotonic saline and glucose, but increased after hypertonic saline (139%). PRC, AngII and p-Aldo decreased after isotonic and hypertonic saline infusion, but not after glucose infusion. CONCLUSIONS Volume expansion with 3% and 0.9% saline increased u-AQP2, while isotonic glucose decreased u-AQP2. Infusion of hypertonic saline increased u-ENaCγ, whereas u-ENaCγ was not significantly changed after isotonic saline and tended to decrease after glucose. Thus, the transport of water and sodium is changed both via the aquaporin 2 water channels and the epithelial sodium channels during all three types of volume expansion to regulate and maintain water- and sodium homeostasis in the body. TRIAL REGISTRATION Clinical Trial no: NCT01414088.
Collapse
Affiliation(s)
- Janni M Jensen
- Department of Medical Research, Holstebro Hospital, Laegaardvej 12, Holstebro 7500, Denmark
- Aarhus University, Aarhus, Denmark
| | - Frank H Mose
- Department of Medical Research, Holstebro Hospital, Laegaardvej 12, Holstebro 7500, Denmark
- Aarhus University, Aarhus, Denmark
| | - Jesper N Bech
- Department of Medical Research, Holstebro Hospital, Laegaardvej 12, Holstebro 7500, Denmark
- Aarhus University, Aarhus, Denmark
| | - Soren Nielsen
- Water and Salt Research Centre, Aarhus University, Aarhus, Denmark
| | - Erling B Pedersen
- Department of Medical Research, Holstebro Hospital, Laegaardvej 12, Holstebro 7500, Denmark
- Aarhus University, Aarhus, Denmark
| |
Collapse
|
|
49
|
Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, Levin A. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 2013; 382:158-69. [PMID: 23727165 DOI: 10.1016/s0140-6736(13)60439-0] [Citation(s) in RCA: 805] [Impact Index Per Article: 67.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinary albumin excretion. Furthermore, an acute reduction in glomerular filtration rate is a risk factor for adverse clinical outcomes and the development and progression of chronic kidney disease. An increasing amount of evidence suggests that the kidneys are not only target organs of many diseases but also can strikingly aggravate or start systemic pathophysiological processes through their complex functions and effects on body homoeostasis. Risk of kidney disease has a notable genetic component, and identified genes have provided new insights into relevant abnormalities in renal structure and function and essential homoeostatic processes. Collaboration across general and specialised health-care professionals is needed to fully address the challenge of prevention of acute and chronic kidney disease and improve outcomes.
Collapse
Affiliation(s)
- Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Roos KP, Bugaj V, Mironova E, Stockand JD, Ramkumar N, Rees S, Kohan DE. Adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity. J Am Soc Nephrol 2013; 24:218-27. [PMID: 23264685 PMCID: PMC3559481 DOI: 10.1681/asn.2012050449] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2012] [Accepted: 10/22/2012] [Indexed: 12/11/2022] Open
Abstract
Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.
Collapse
Affiliation(s)
- Karl P. Roos
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah; and
| | - Vladislav Bugaj
- Department of Physiology, University of Texas Health Sciences Center, San Antonio, Texas
| | - Elena Mironova
- Department of Physiology, University of Texas Health Sciences Center, San Antonio, Texas
| | - James D. Stockand
- Department of Physiology, University of Texas Health Sciences Center, San Antonio, Texas
| | - Nirupama Ramkumar
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah; and
| | - Sara Rees
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah; and
| | - Donald E. Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah; and
| |
Collapse
|