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https://www.readbyqxmd.com/read/29036630/resequencing-epithelial-sodium-channel-genes-identifies-rare-variants-associated-with-blood-pressure-salt-sensitivity-the-gensalt-study
#1
Xiaoying Gu, Dongfeng Gu, Jiang He, Dabeeru C Rao, James E Hixson, Jichun Chen, Jianxin Li, Jianfeng Huang, Xigui Wu, Treva K Rice, Lawrence C Shimmin, Tanika N Kelly
BACKGROUND: A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with BP salt-sensitivity. METHODS: The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study...
September 19, 2017: American Journal of Hypertension
https://www.readbyqxmd.com/read/29035132/hybrid-lipid-polymer-nanoparticles-for-pulmonary-delivery-of-sirna-development-and-fate-upon-in-vitro-deposition-on-the-human-epithelial-airway-barrier
#2
Ivana d'Angelo, Gabriella Costabile, Estelle Durantie, Paola Brocca, Valeria Rondelli, Annapina Russo, Giulia Russo, Agnese Miro, Fabiana Quaglia, Alke Petri-Fink, Barbara Rothen-Rutishauser, Francesca Ungaro
BACKGROUND: Nowadays, the downregulation of genes involved in the pathogenesis of severe lung diseases through local siRNA delivery appears an interesting therapeutic approach. In this study, we propose novel hybrid lipid-polymer nanoparticles (hNPs) consisting of poly(lactic-co-glycolic) acid (PLGA) and dipalmitoyl phosphatidylcholine (DPPC) as siRNA inhalation system. METHODS: A panel of DPPC/PLGA hNPs was prepared by emulsion/solvent diffusion and fully characterized...
October 16, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/29021227/physiological-regulation-of-the-epithelial-na-channel-by-casein-kinase-ii
#3
Jonathan M Berman, Elena Mironova, James D Stockand
The Epithelial Na+ Channel, ENaC, is the final arbiter of sodium excretion in the kidneys. As such, discretionary control of ENaC by hormones is critical to the fine-tuning of electrolyte and water excretion and consequently, blood pressure. Casein kinase 2 (CK2) phosphorylates ENaC. Phosphorylation by CK2 is necessary for normal ENaC activity. We tested the physiological importance of CK2 regulation of ENaC as the degree to which ENaC activity is dependent on CK2 phosphorylation in the living organism is unknown...
October 11, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28985241/short-term-high-salt-diet-increases-corin-level-to-regulate-the-salt-water-balance-in-humans-and-rodents
#4
Jiao Zhang, Yanjun Yin, Lili Chen, Chao Chu, Yang Wang, Yongbo Lv, Ming He, Marcy Martin, Po-Hsun Huang, Jian-Jun Mu, John Y-J Shyy, Zu-Yi Yuan
Background: Dietary sodium and potassium affect the fluctuation in blood pressure and renal function. Corin, with its enzymatic activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, regulates blood pressure, cardiac and renal functions. We investigated whether corin expression responds to a high-salt (HS) diet to regulate salt and water balance. Methods and results: Forty-two volunteers followed 3 sequential diets for 7 days each: a low-salt (LS) diet (3...
August 8, 2017: American Journal of Hypertension
https://www.readbyqxmd.com/read/28984146/nonclinical-safety-assessment-of-spx-101-a-novel-peptide-promoter-of-epithelial-sodium-channel-internalization-for-the-treatment-of-cystic-fibrosis
#5
Matthew P Walker, Matt Cowlen, Dale Christensen, Mutsumi Miyamoto, Phillip Barley, Timothy Crowder
BACKGROUND: ENaC inhibition has long been an attractive therapeutic target for the treatment of cystic fibrosis. However, previous attempts at developing ENaC inhibitors have been unsuccessful due to complications arising from systemic circulation of the compounds. Here, we describe the preclinical toxicology assessment of a new inhaled peptide promoter of ENaC internalization delivered as a nebulized aerosol. METHODS: Preclinical assessment of SPX-101 safety was determined using an in vitro hERG assay, bolus injection of SPX-101 in a canine cardiovascular and respiratory safety pharmacology model and 28-day inhalation toxicology studies of nebulized drug in rats and dogs...
October 6, 2017: Inhalation Toxicology
https://www.readbyqxmd.com/read/28982737/evaluation-of-a-splunc1-derived-peptide-for-the-treatment-of-cystic-fibrosis-lung-disease
#6
Shawn T Terryah, Robert C Fellner, Saira Ahmad, Patrick John Moore, Boris Reidel, Juliana I Sesma, Christine S Kim, Alaina L Garland, David W Scott, Juan R Sabater, Jerome Carpenter, Scott H Randell, Mehmet Kesimer, William M Abraham, William J Arendshorst, Robert Tarran
In cystic fibrosis (CF) lungs, epithelial Na+ channel (ENaC) hyperactivity causes a reduction in airway surface liquid (ASL) volume, leading to decreased mucocilliary clearance and lung damage. Inhibition of ENaC is an attractive therapeutic option. However, ENaC antagonists have failed clinically due to off-target renal effects. The S18 peptide is a naturally occurring short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived ENaC antagonist that restores ASL height for up to 24 h in CF human bronchial epithelial cultures...
October 5, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28981824/thirst-increases-chorda-tympani-responses-to-sodium-chloride
#7
Thomas G Mast, Joseph M Breza, Robert J Contreras
In nature, water is present as a low-salt solution, thus we hypothesized that thirst would increase taste responses to low-salt solutions. We investigated the effect of thirst on the 2 different salt detection mechanisms present in the rat chorda tympani (CT) nerve. The first mechanism is dependent upon the epithelial sodium channel (ENaC), is blocked by benzamil, and is specific to the cation sodium. The second mechanism, while undefined, is independent of ENaC, and detects multiple cations. We expected thirst to increase benzamil-sensitive sodium responses due to mechanistically increasing the benzamil-sensitive ENaC...
October 1, 2017: Chemical Senses
https://www.readbyqxmd.com/read/28981267/salivary-proteome-patterns-affecting-human-salt-taste-sensitivity
#8
Theresa Stolle, Freya Grondinger, Andreas Dunkel, Chen Meng, Guillaume Médard, Bernhard Kuster, Thomas Hofmann
In order to investigate the role of perireceptor events in inter-individual variability in salt taste sensitivity, 31 volunteers were monitored in their detection functions for sodium chloride (NaCl) and classified into sensitive (0.6 - 1.7 mmol/L), medium sensitive (1.8 - 6.9 mmol/L), and non-sensitive subjects (7.0 - 11.2 mmol/L). Chemosensory intervention of NaCl sensitive (S+) and non-sensitive panellists (S-) with potassium chloride, ammonium chloride, and sodium gluconate, respectively, showed the salt-taste sensitivity to be specific for NaCl...
October 5, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28978526/loss-of-inversin-decreases-transepithelial-sodium-transport-in-murine-renal-cells
#9
Nalini H Kulkarni, Rosamund C Smith, Bonnie L Blazer-Yost
Type II nephronophthisis (NPHP2) is an autosomal recessive renal cystic disorder characterized by mutations in the inversin gene. Humans and mice with mutations in inversin have enlarged cystic kidneys that may be due to fluid accumulation resulting from altered ion transport. To address this, transepithelial ion transport was measured in shRNA mediated inversin-depleted mouse cortical collecting duct (mCCD) cells. Loss of inversin decreased the basal ion flux in mCCD cells compared to controls. Depletion of inversin decreased vasopressin-induced Na+ absorption, but did not alter Cl- secretion by mCCD cells...
October 4, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28954214/changes-in-plasma-aldosterone-and-electrolytes-levels-kidney-epithelial-sodium-channel-enac-and-blood-pressure-in-normotensive-wky-and-hypertensive-shr-rats-following-gonadectomy-and-chronic-testosterone-treatment
#10
Su Yi Loh, Nelli Giribabu, Naguib Salleh
We hypothesized that testosterone-induced increase in blood pressure involve changes in aldosterone levels and expression of epithelial sodium channel (ENaC) in the kidneys. METHODS: Ovariectomized female normotensive Wistar Kyoto (WKY) and Spontaneous hypertensive (SHR) rats were given six weeks treatment with testosterone via subcutaneous silastic implant. The rats were anesthetized and mean arterial pressure (MAP) was measured via direct cannulation of the carotid artery. Animals were sacrificed and kidneys were removed and subjected for α, β and γ-ENaC protein and mRNA expression analyses by Western blotting and Real-time polymerase chain reaction (qPCR), respectively...
September 24, 2017: Steroids
https://www.readbyqxmd.com/read/28950003/the-endothelial-%C3%AE-enac-contributes-to-vascular-endothelial-function-in-vivo
#11
Antoine Tarjus, Martina Maase, Pia Jeggle, Ernesto Martinez-Martinez, Céline Fassot, Laurent Loufrani, Daniel Henrion, Pernille B L Hansen, Kristina Kusche-Vihrog, Frederic Jaisser
The Epithelial Sodium Channel (ENaC) is a key player in renal sodium homeostasis. The expression of α β γ ENaC subunits has also been described in the endothelium and vascular smooth muscle, suggesting a role in vascular function. We recently demonstrated that endothelial ENaC is involved in aldosterone-modulated endothelial stiffness. Here we explore the functional role of the endothelial αENaC subunit in vascular function in vivo. Compared to littermates, mice with conditional αENaC subunit gene inactivation in the endothelium only (endo-αENaC Knock Out mice) had no difference in their physiological parameters such as systolic blood pressure or heart rate...
2017: PloS One
https://www.readbyqxmd.com/read/28940314/dietary-sodium-induces-a-redistribution-of-the-tubular-metabolic-workload
#12
Khalil Udwan, Ahmed Abed, Isabelle Roth, Eva Dizin, Marc Maillard, Carla Bettoni, Johannes Loffing, Carsten A Wagner, Aurélie Edwards, Eric Feraille
Na(+) excretion by the kidney varies according to dietary Na(+) intake. We undertook a systematic study on the effects of dietary salt intake on glomerular filtration rate (GFR) and tubular Na(+) reabsorption. We examined the renal adaptive response in mice subjected to 7 days of a low sodium diet (LSD) containing 0.01% Na(+) , a normal sodium diet (NSD) containing 0.18% Na(+) , as well as a moderately high sodium diet (HSD) containing 1.25% Na(+) . As expected, LSD did not alter measured GFR and increased the abundance of total and cell-surface NHE3, NKCC2, NCC, α-ENaC, and cleaved γ-ENaC compared to NSD...
September 20, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28890943/trial-of-amiloride-in-type-2-diabetes-with-proteinuria
#13
Mark L Unruh, V Shane Pankratz, John E Demko, Evan C Ray, Rebecca P Hughey, Thomas R Kleyman
INTRODUCTION: Renal Na(+) retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome, which occurs even in the absence of activation of hormones that stimulate renal Na(+) transporters. Plasmin-dependent activation of the epithelial Na(+) channel (ENaC) has been proposed to have a role in renal Na(+) retention in the setting of nephrotic syndrome. We hypothesized that the ENaC inhibitor amiloride would be an effective therapeutic agent in inducing a natriuresis and lowering blood pressure in individuals with macroscopic proteinuria...
September 2017: KI Reports
https://www.readbyqxmd.com/read/28877879/uninephrectomy-and-apical-fluid-shear-stress-decrease-enac-abundance-in-collecting-duct-principal-cells
#14
Thomas Ernandez, Khalil Udwan, Alexandra Chassot, Pierre-Yves Martin, Eric Feraille
Acute nephron reduction such as after living kidney donation may increase the risk of hypertension. Uninephrectomy induces major hemodynamic changes in the remaining kidney resulting in rapid increase of single nephron GFR and fluid delivery in the distal nephron. Decreased sodium (Na) fractional reabsorption after the distal tubule has been reported after uninephrectomy in animals preserving volume homeostasis. In the present study, we thought to specifically explore the effect of unilateral nephrectomy on ENaC subunits expression in mice...
September 6, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28876128/influence-of-inhaled-amiloride-on-lung-fluid-clearance-in-response-to-normobaric-hypoxia-in-healthy-individuals
#15
Courtney M Wheatley, Sarah E Baker, Bryan J Taylor, Manda L Keller-Ross, Steven C Chase, Alex R Carlson, Robert J Wentz, Eric M Snyder, Bruce D Johnson
Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 00:000-000, 2017. AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12...
September 6, 2017: High Altitude Medicine & Biology
https://www.readbyqxmd.com/read/28862701/deletion-of-nedd4-2-results-in-progressive-kidney-disease-in-mice
#16
Tanya L Henshall, Jantina A Manning, Omri S Alfassy, Pranay Goel, Natasha A Boase, Hiroshi Kawabe, Sharad Kumar
NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na(+) channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na(+)Cl(-) cotransporter expression, increased Na(+) reabsorption, hypertension and markedly reduced levels of aldosterone...
September 1, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28861610/inhibitors-of-the-proteasome-stimulate-the-epithelial-sodium-channel-enac-through-sgk1-and-mimic-the-effect-of-aldosterone
#17
Morag K Mansley, Christoph Korbmacher, Marko Bertog
The epithelial sodium channel (ENaC) marks the tightly regulated, rate-limiting step of sodium re-absorption in the aldosterone-sensitive distal nephron (ASDN). Stimulation of ENaC activity by aldosterone involves the serum and glucocorticoid-induced kinase 1 (SGK1) and is mediated via complex mechanisms including inhibition of channel retrieval. Retrieved channels may be recycled or degraded, e.g. by the proteasomal pathway. The aim of the present study was to investigate whether inhibitors of the proteasome affect ENaC activity and surface expression, and to explore a possible involvement of SGK1...
August 31, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28835421/effect-of-salt-intake-on-afferent-arteriolar-dilatation-role-of-connecting-tubule-glomerular-feedback-ctgf
#18
Hong Wang, Cesar A Romero, J X Masjoan Juncos, Sumit R Monu, Edward L Peterson, Oscar A Carretero
Afferent arteriole (Af-Art) resistance is modulated by 2 intrinsic nephron feedbacks: 1) vasoconstrictor tubuloglomerular feedback (TGF), which is mediated by NKCC2 in the macula densa and blocked by furosemide; and 2) vasodilator connecting tubule glomerular feedback (CTGF), which is mediated by ENaC in the connecting tubule and blocked by benzamil. High salt intake reduces the Af-Art vasoconstrictor ability in Dahl salt-sensitive rats (Dahl SS). Previously, we measured CTGF indirectly using the differences between the TGF responses with and without CTGF inhibition...
August 23, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28834749/composition-and-control-of-a-deg-enac-channel-during-presynaptic-homeostatic-plasticity
#19
Brian O Orr, David Gorczyca, Meg A Younger, Lily Y Jan, Yuh-Nung Jan, Graeme W Davis
The homeostatic control of presynaptic neurotransmitter release stabilizes information transfer at synaptic connections in the nervous system of organisms ranging from insect to human. Presynaptic homeostatic signaling centers upon the regulated membrane insertion of an amiloride-sensitive degenerin/epithelial sodium (Deg/ENaC) channel. Elucidating the subunit composition of this channel is an essential step toward defining the underlying mechanisms of presynaptic homeostatic plasticity (PHP). Here, we demonstrate that the ppk1 gene encodes an essential subunit of this Deg/ENaC channel, functioning in motoneurons for the rapid induction and maintenance of PHP...
August 22, 2017: Cell Reports
https://www.readbyqxmd.com/read/28814438/collecting-duct-prorenin-receptor-knockout-reduces-renal-function-increases-na-excretion-and-mitigates-renal-responses-in-angii-induced-hypertensive-mice
#20
Minolfa C Prieto, Virginia Reverte, Mykola Mamenko, Marta Kuczeriska, Luciana C Veiras, Carla B Rosales, Matthew McLellan, Oliver Gentile, V Behrana Jensen, Atsuhiro Ichihara, Alicia A McDonough, Oleh M Pochynyuk, Alexis A Gonzalez
Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANGII-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial...
August 16, 2017: American Journal of Physiology. Renal Physiology
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