Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Abstract

In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.

Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis

“…CTS belongs to a group of volume-sensitive hormones [91] that seem to be both sufficient to alter transmembrane sodium transport in some cell types as well as to provoke a variety of cellular signals [92]. CTS can be structurally divided into two distinct categories, cardenolides that include ouabain and digoxin, and bufadienolides that includes telocinobufagin and marinobufagenin [91,93]. The synthesis and release of CTS are controlled by volume expansion and salt concentration, while it is regulated by the hormones of the hypothalamic-pituitary-adrenal axis [93,94].…”

“…Once released into the blood, CTS may have varying effects on different tissues throughout the body [95][96][97]. Differing concentrations of CTS allow for varying degrees of response [91,96,98]. Despite contentions, endogenous CTS represents an essential class of hormones with profound outcomes in health and disease [99,100].…”

“…Several pathways and mechanisms have been described to unravel molecular mechanisms involved in the pathogenesis of liver fibrosis [15,48,[158][159][160]. Elevated levels of circulating CTS potentially contribute to disease progression, such as in various chronic inflammatory conditions like obesity, hypertension, NASH, cardiovascular disease, and further stimulate the proinflammatory and profibrotic response [91][92][93]99,102,[161][162][163][164]. Numerous studies have examined the role of the Na/K-ATPase ascribed by the scaffolding and signaling function in mediating organ fibrosis [91,101,165].…”

Predicting Nonalcoholic Fatty Liver Disease through a Panel of Plasma Biomarkers and MicroRNAs in Female West Virginia Population

“…Apart from these well-established mechanisms of hepatic fibrosis and disease progression, cumulative clinical and experimental evidence present in the literature suggests a role of cardiotonic steroids in mediating prooxidant and profibrotic effects in hepatic tissue [15][16][17][18][19][20][21][22]. While the hepatic tissue is a primary site for the maintenance of cholesterol homeostasis [23], studies have suggested an important role of cardiotonic steroids in regulation of cholesterol biosynthesis [24,25].…”

Estudo bioquímico comparativo da (Na+ , K+)-ATPase branquial de Macrobrachium amazonicum (Heller, 1862) habitante de regiões continentais

“…A participação da enzima em diferentes níveis de organização fisiológica necessita de uma coordenação precisa de suas funções na célula, nos órgãos, bem como em todo o organismo (Pirkmajer & Chibalin, 2016;2019). Devido a sua abundância nos mais diversos tipos celulares a (Na + , K + )-ATPase apresenta uma grande importância em diversas doenças e seus diferentes reguladores podem apresentar um grande valor terapêutico (Aperia, 2007;Slingerland et al, 2013;Holm et al, 2016;Ziff & Kotecha, 2016;Clausen et al, 2017;Obradovic et al, 2017;Amarelle & Lecuna, 2018;Bolotta et al, 2018;Khalaf et al, 2018;Pivovarov et al, 2019;Orlov et al, 2019).…”