The Redox-Sensitive Na/K-ATPase Signaling in Uremic Cardiomyopathy

In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.

• Publication year

  2020

• Venue

  International Journal of Molecular Sciences

• Publication date

  2020-02-01

• Fields of study

  Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.3390/ijms21041256PMID 32069992PMCID 7072896
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Clinical Significance

  2020cited by this paper
• Cardiorenal Syndrome

  2020cited by this paper
• Evolving concepts in the pathogenesis of uraemic cardiomyopathy

  2019cited by this paper
• RETRACTED ARTICLE: The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities

  2019cited by this paper
• RETRACTED: Uremic Toxins Activates Na/K-ATPase Oxidant Amplification Loop Causing Phenotypic Changes in Adipocytes in In Vitro Models

  2018cited by this paper
• Na/K-ATPase signaling mediates miR-29b-3p regulation and cardiac fibrosis formation in mice with chronic kidney disease

  2018cited by this paper
• The Na/K-ATPase Signaling: From Specific Ligands to General Reactive Oxygen Species

  2018cited by this paper
• RETRACTED ARTICLE: The Na/K-ATPase Oxidant Amplification Loop Regulates Aging

  2018cited by this paper
• A Mouse 5/6th Nephrectomy Model That Induces Experimental Uremic Cardiomyopathy.

  2017cited by this paper
• Cysteine residues 244 and 458–459 within the catalytic subunit of Na,K-ATPase control the enzyme's hydrolytic and signaling function under hypoxic conditions

  2017cited by this paper
• RETRACTED ARTICLE: pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet

  2017cited by this paper
• Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts.

  2016cited by this paper
• Differential roles of caveolin-1 in ouabain-induced Na+/K+-ATPase cardiac signaling and contractility.

  2016cited by this paper
• Protein Carbonylation of an Amino Acid Residue of the Na/K‐ATPase α1 Subunit Determines Na/K‐ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells

  2016cited by this paper
• Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro‐Fibrotic Signaling

  2016cited by this paper
• “Oxygen Sensing” by Na,K-ATPase: These Miraculous Thiols

  2016cited by this paper
• Attenuation of Na/K-ATPase Mediated Oxidant Amplification with pNaKtide Ameliorates Experimental Uremic Cardiomyopathy

  2016cited by this paper
• Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase α in mouse

  2015cited by this paper
• Mitochondrial dysfunction in uremic cardiomyopathy.

  2015cited by this paper
• Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure

  2015cited by this paper
• Reduction of Na/K-ATPase affects cardiac remodeling and increases c-kit cell abundance in partial nephrectomized mice.

  2014cited by this paper
• Involvement of Na/K-ATPase in hydrogen peroxide-induced activation of the Src/ERK pathway in LLC-PK1 cells.

  2014cited by this paper
• Involvement of Reactive Oxygen Species in a Feed-forward Mechanism of Na/K-ATPase-mediated Signaling Transduction*

  2013cited by this paper
• Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy.

  2013cited by this paper
• S-Glutathionylation of the Na,K-ATPase Catalytic α Subunit Is a Determinant of the Enzyme Redox Sensitivity*

  2012cited by this paper
• Oxidative stress, anti‐oxidant therapies and chronic kidney disease

  2012cited by this paper
• Susceptibility of β1 Na+-K+ Pump Subunit to Glutathionylation and Oxidative Inhibition Depends on Conformational State of Pump*

  2012cited by this paper
• Renal Redox Balance and Na+, K+-ATPase Regulation: Role in Physiology and Pathophysiology

  2012cited by this paper
• Reduction of Na/K-ATPase Potentiates Marinobufagenin-induced Cardiac Dysfunction and Myocyte Apoptosis*

  2012cited by this paper
• Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure.

  2012cited by this paper
• Oxidative regulation of the Na(+)-K(+) pump in the cardiovascular system.

  2012cited by this paper
• Na/K-ATPase Mimetic pNaKtide Peptide Inhibits the Growth of Human Cancer Cells*

  2011cited by this paper
• FXYD Proteins Reverse Inhibition of the Na+-K+ Pump Mediated by Glutathionylation of Its β1 Subunit*

  2011cited by this paper
• Endogenous cardiotonic steroids in chronic renal failure.

  2011cited by this paper
• Chronic Kidney Disease-Induced Cardiac Fibrosis Is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uremic Toxin, Indoxyl Sulfate

  2011cited by this paper
• Definition and classification of Cardio-Renal Syndromes: workgroup statements from the 7th ADQI Consensus Conference.

  2010cited by this paper
• Cardiorenal Syndrome: New Perspectives

  2010cited by this paper
• Alterations of Na+/K+-ATPase function in caveolin-1 knockout cardiac fibroblasts.

  2010cited by this paper
• Is oxidative stress a therapeutic target in cardiovascular disease?

  2010cited by this paper
• Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin

  2009cited by this paper
• NaKtide, a Na/K-ATPase-derived Peptide Src Inhibitor, Antagonizes Ouabain-activated Signal Transduction in Cultured Cells*

  2009cited by this paper
• Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets

  2009cited by this paper
• The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition.

  2009cited by this paper
• Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy.

  2009cited by this paper
• Reversible Oxidative Modification: A Key Mechanism of Na+-K+ Pump Regulation

  2009influential reference
• Angiotensin II inhibits the Na+-K+ pump via PKC-dependent activation of NADPH oxidase.

  2009cited by this paper
• The reactive nitrogen species peroxynitrite is a potent inhibitor of renal Na-K-ATPase activity.

  2008cited by this paper
• Cardiorenal syndrome.

  2008cited by this paper
• The Na/K-ATPase/Src complex and cardiotonic steroid-activated protein kinase cascades

  2008cited by this paper
• Endogenous digitalis: pathophysiologic roles and therapeutic applications

  2008cited by this paper
• Effects of cardiotonic steroids on dermal collagen synthesis and wound healing.

  2008cited by this paper
• Partial nephrectomy as a model for uremic cardiomyopathy in the mouse.

  2008cited by this paper
• Regulation of apical NHE3 trafficking by ouabain-induced activation of the basolateral Na+-K+-ATPase receptor complex.

  2008cited by this paper
• Regulation of Inositol 1,4,5-Trisphosphate Receptor-mediated Calcium Release by the Na/K-ATPase in Cultured Renal Epithelial Cells*

  2008cited by this paper
• Lipid Rafts Keep NADPH Oxidase in the Inactive State in Human Renal Proximal Tubule Cells

  2008cited by this paper
• Role of endogenous cardiotonic steroids in sodium homeostasis.

  2008cited by this paper
• Association of PI3K-Akt signaling pathway with digitalis-induced hypertrophy of cardiac myocytes.

  2007cited by this paper
• Marinobufagenin Stimulates Fibroblast Collagen Production and Causes Fibrosis in Experimental Uremic Cardiomyopathy

  2007cited by this paper
• Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth.

  2007cited by this paper
• New roles for an old enzyme: Na,K‐ATPase emerges as an interesting drug target

  2007cited by this paper
• The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference

  2006cited by this paper
• Lipid rafts take center stage in endothelial cell redox signaling by death receptors.

  2006cited by this paper
• Central Role for the Cardiotonic Steroid Marinobufagenin in the Pathogenesis of Experimental Uremic Cardiomyopathy

  2006cited by this paper
• Na-K-ATPase in rat cerebellar granule cells is redox sensitive.

  2006cited by this paper
• N‐acetylcysteine attenuates the decline in muscle Na+,K+‐pump activity and delays fatigue during prolonged exercise in humans

  2006cited by this paper
• Hypoxia-Mediated Degradation of Na,K-ATPase via Mitochondrial Reactive Oxygen Species and the Ubiquitin-Conjugating System

  2006cited by this paper
• Ouabain decreases sarco(endo)plasmic reticulum calcium ATPase activity in rat hearts by a process involving protein oxidation.

  2006cited by this paper
• UNRESOLVED ISSUES IN DIALYSIS: Extracorporeal Strategies for the Removal of Middle Molecules

  2006cited by this paper
• Oxygen- and Redox-Induced Regulation of the Na/K ATPase

  2006cited by this paper
• Involvement of Na+/K+-ATPase in hydrogen peroxide-induced hypertrophy in cardiac myocytes.

  2006cited by this paper
• Lipid Raft Clustering and Redox Signaling Platform Formation in Coronary Arterial Endothelial Cells

  2006cited by this paper
• Ouabain-induced endocytosis of the plasmalemmal Na/K-ATPase in LLC-PK1 cells requires caveolin-1.

  2005cited by this paper
• Uremic cardiomyopathy: role of circulating digitalis like substances.

  2005cited by this paper
• Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex.

  2005cited by this paper
• A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure.

  2005influential reference
• Na(+)--Ca2+ exchange in the regulation of cardiac excitation-contraction coupling.

  2005cited by this paper
• Caveolin-1 Is Essential for Activation of Rac1 and NAD(P)H Oxidase After Angiotensin II Type 1 Receptor Stimulation in Vascular Smooth Muscle Cells: Role in Redox Signaling and Vascular Hypertrophy

  2005cited by this paper
• Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism.

  2004cited by this paper
• Organ Hypertrophic Signaling within Caveolae Membrane Subdomains Triggered by Ouabain and Antagonized by PST 2238*

  2004cited by this paper
• Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 cells.

  2004cited by this paper
• Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance?

  2004cited by this paper
• Involvement of mitogen-activated protein kinases and reactive oxygen species in the inotropic action of ouabain on cardiac myocytes. A potential role for mitochondrial KATP channels

  2004cited by this paper
• Effect of green tea extract on cardiac hypertrophy following 5/6 nephrectomy in the rat.

  2003cited by this paper
• Global Loss of Na,K-ATPase and Its Nitric Oxide-Mediated Regulation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

  2003cited by this paper
• The Na, K-ATPase in the failing human heart.

  2003cited by this paper
• Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta.

  2003cited by this paper
• Effect of chronic renal failure on cardiac contractile function, calcium cycling, and gene expression of proteins important for calcium homeostasis in the rat.

  2003cited by this paper
• Cell Signaling Microdomain with Na,K-ATPase and Inositol 1,4,5-Trisphosphate Receptor Generates Calcium Oscillations*

  2003cited by this paper
• Na/K-ATPase regulates intracellular ROS level in cerebellum neurons.

  2003cited by this paper
• c-Src Induces Phosphorylation and Translocation of p47phox: Role in Superoxide Generation by Angiotensin II in Human Vascular Smooth Muscle Cells

  2003cited by this paper
• Ouabain suppresses glucose-induced mitochondrial ATP production and insulin release by generating reactive oxygen species in pancreatic islets.

  2002cited by this paper
• Peroxynitrite and the regulation of Na(+),K(+)-ATPase activity by angiotensin II in the rat proximal tubule.

  2002cited by this paper
• Angiotensin II Stimulation of NAD(P)H Oxidase Activity: Upstream Mediators

  2002cited by this paper
• Src-mediated Inter-receptor Cross-talk between the Na+/K+-ATPase and the Epidermal Growth Factor Receptor Relays the Signal from Ouabain to Mitogen-activated Protein Kinases*

  2002cited by this paper
• Endogenous cardiac glycosides, a new class of steroid hormones.

  2002cited by this paper
• Ouabain, a steroid hormone that signals with slow calcium oscillations

  2001cited by this paper
• Ouabain-induced Signaling and Vascular Smooth Muscle Cell Proliferation*

  2001cited by this paper
• Effects of uremic serum on isolated cardiac myocyte calcium cycling and contractile function.

  2001cited by this paper
• Signal-transducing function of Na+-K+-ATPase is essential for ouabain's effect on [Ca2+]i in rat cardiac myocytes.

  2001cited by this paper
• Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+/K+-ATPase.

  2000cited by this paper

• Investigation of Neuroprotective Qualities of Saraca asoca Methanolic Leaf Extract Against Diabetes-induced Peripheral Neuropathy in Rat Model

  2025cites this paper
• The astrocytic engine: Na+,K+-ATPase at the nexus of brain function and malfunction.

  2025cites this paper
• Factors Influencing Digoxin Efficacy in Supraventricular Tachyarrhythmia: The Role of Hemoglobin and Renal Function

  2025cites this paper
• Redox Homeostasis in Red Blood Cells: From Molecular Mechanisms to Antioxidant Strategies

  2025cites this paper
• Oxidative Stress in the Regulation of Autosis-Related Proteins

  2025cites this paper
• Factors that influence the Na/K-ATPase signaling and function

  2025cites this paper
• Polystyrene microplastics with absorbed nonylphenol induce intestinal dysfunction in human Caco-2 cells.

  2024cites this paper
• Na+/K+-ATPase: More than an Electrogenic Pump

  2024cites this paper
• NMDA Receptors and Indices of Energy Metabolism in Erythrocytes: Missing Link to the Assessment of Efficiency of Oxygen Transport in Hepatic Encephalopathy

  2024cites this paper
• Interplay between the Redox System and Renal Tubular Transport

  2024cites this paper
• Oxidative Stress Markers and Na,K-ATPase Enzyme Kinetics Are Altered in the Cerebellum of Zucker Diabetic Fatty fa/fa Rats: A Comparison with Lean fa/+ and Wistar Rats

  2024cites this paper
• Digoxin and its Na+/K+-ATPase-targeted actions on cardiovascular diseases and cancer.

  2024cites this paper
• Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation

  2023cites this paper
• Migraine‐Associated Mutation in the Na,K‐ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function

  2022cites this paper
• Pumpkin seed oil and zinc attenuate chronic mild stress perturbations in the cerebral cortex of rats

  2022cites this paper
• Modification of Ischemia/Reperfusion-Induced Alterations in Subcellular Organelles by Ischemic Preconditioning

  2022cites this paper
• Blockage of Na/K-ATPase oxidant amplification loop elongates red blood cell half-life and ameliorates uremic anemia induced by PNx in C57BL/6 mice.

  2022cites this paper
• Cardiac metabolic remodelling in chronic kidney disease

  2022cites this paper
• A Bibliometric and Visualized Analysis of Uremic Cardiomyopathy From 1990 to 2021

  2022cites this paper
• Na+/K+-ATPase DR region antibody ameliorated cardiac hypertrophy and fibrosis in rats with 5/6 nephrectomy

  2022cites this paper
• The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?

  2021cites this paper
• Targeting Na+/K+‐ATPase by berbamine and ouabain synergizes with sorafenib to inhibit hepatocellular carcinoma

  2021cites this paper
• Erythrocyte Deformability and Na,K-ATPase Activity in Various Pathophysiological Situations and Their Protection by Selected Nutritional Antioxidants in Humans

  2021cites this paper
• The Potential Role of the Na/K-ATPase and its Signaling in Development of Anemia in Chronic Kidney Disease.

  2020cites this paper