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

Abstract

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.

The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?

“…A culprit is that the Na/K-ATPase signaling may increase ROS generation, whereas the SGLT2 inhibitor reduces oxidative stress. Since the Na/K-ATPase signaling is redox-sensitive (Liu et al 2020 ), overstimulated signaling may chronically desensitize the signaling function and reduce Na/K-ATPase ion-transport capability by stimulating Na/K-ATPase/c-Src endocytosis. In clinical trials with antioxidant supplements, on the other side, the beneficial effect is controversial and not seen in most of the trials (Huang et al 2006 ; Munzel et al 2010 ; Touyz 2004 ).…”

“…A feed-forward, redox-sensitive Na/K-ATPase signaling-mediated oxidant amplification loop, stimulated either by CTS or ROS (Pratt et al 2018 ). The Na/K-ATPase signaling and its amplification loop play an essential role in the regulation of cardiac hypertrophy, salt-sensitive hypertension in both Dahl salt-sensitive rats and polygenic obese TALLYHO/JngJ mice (a mouse model mimics the state of obesity in humans with a polygenic background of type 2 diabetes), RPT Na + reabsorption, systemic redox status, experimental CKD-induced cardiomyopathy (including left ventricle hypertrophy and cardiac/renal fibrosis) and anemia (Liu et al 2020 , 2016a , 2011 , 2016b ; Pratt et al 2018 ; Sodhi et al 2020 ; Wang and Shapiro 2019 ; Yan et al 2019 ). However, it worth noting that this positive feedback mechanism might chronically desensitize the signaling function and reduce Na/K-ATPase ion-transport capability by stimulating Na/K-ATPase/c-Src endocytosis (Cai et al 2008 ; Liu et al 2004 , 2005 ).…”

“…Recent studies demonstrated that overstimulation of Na/K-ATPase signaling by increased endogenous CTS causes elevation of oxidative stress, which may play an important role in the uremic cardiomyopathy, including cardiac hypertrophy and cardiac fibrosis (Liu et al 2020 ; Sodhi et al 2020 ; Wang et al 2020 ). In addition, low doses of CTS induced hypertension in rats and caused significant CV remodeling independent of their effect on blood pressure (Ferrandi et al 2004 ; Jiang et al 2007 ; Kennedy et al 2006 ; Skoumal et al 2007 ).…”

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

“…The activity of the Na,K-ATPase in erythrocytes of patients was more times suggested as a biomarker with potential prognostic value for estimating the severity of various diseases. It is also well known that the functionality of this enzyme decreases in oxidative stress conditions [ 11 , 12 ]. More specifically, the oxidative stress-induced modifications of the Na,K-ATPase enzyme include its glutathionylation, nitrosylation, phosphorylation and carbonylation that are resulting in the conformation change and in decrease in enzyme activity [ 11 ].…”

“…It is also well known that the functionality of this enzyme decreases in oxidative stress conditions [ 11 , 12 ]. More specifically, the oxidative stress-induced modifications of the Na,K-ATPase enzyme include its glutathionylation, nitrosylation, phosphorylation and carbonylation that are resulting in the conformation change and in decrease in enzyme activity [ 11 ]. Thus, antioxidants have been proposed as substances beneficial for the protection of Na,K-ATPase functions as well as for the erythrocyte condition in general.…”