The Trade-Off between Dietary Salt and Cardiovascular Disease; A Role for Na/K-ATPase Signaling?

Abstract

It has been postulated for some time that endogenous digitalis-like substances, also called cardiotonic steroids (CTS), exist, and that these substances are involved in sodium handling. Within the past 20 years, these substances have been unequivocally identified and measurements of circulating and tissue concentrations have been made. More recently, it has been identified that CTS also mediate signal transduction through the Na/K-ATPase, and consequently been implicated in profibrotic pathways. This review will discuss the mechanism of CTS in renal sodium handling and a potential "trade-off" effect from their role in inducing tissue fibrosis.

Keywords: cardiotonic steroids; digitalis-like factors; fibrosis; hypertension; renal failure; signaling; sodium pump.

Figure 1

The schematic in figure demonstrates Bricker’s proposed trade-off mechanism by which physiologic changes such as reduced glomerular filtration rate (GFR) leading to the increased generation of a hormone can produce the desired effect in solute homeostasis, but with untoward effects in renal and other tissues.

Figure 2

A schematic illustrating the involvement of cardiotonic steroid (CTS) – induced Na/K-ATPase signal cascade initiated by the Na/K-ATPase mediated activation of Src tyrosine kinase and subsequent downstream targets eventually leading to the development of reactive oxygen species (ROS). Specifically, we postulate that in the microdomain of caveolae, the Na/K-ATPase functions as a scaffolding protein, interacting with CTS and changing conformation so as to active Src. Src then trans-activates the EGFR which leads to a signal cascade involving FAK, Shc, Grb2, and SOS resulting in the generation of ROS which in turn activates additional Na/K-ATPase molecules as well as causes downstream activation of ERK as well as effects on the nuclear transcription (43). ERK activation has effects on both L-type channels and possibly the Na/Ca exchanger with net effect to increase cytosolic Ca in some tissues (15). Nuclear effects in myocardial tissue include downregulation of SERCA transcription and translation (70). Abbreviations: EGFR, epidermal growth factor receptor; FAK, focal adhesion kinase; Shc, Src homology-2 domain containing protein; Grb2, growth factor receptor-bound protein-2; SOS, son of sevenless protein; ERK, extracellular-signal-regulated kinase; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase.

Figure 3

The schematic shown in figure illustrates the balance between the natriuretic effect of cardiotonic steroids (CTS) and the trade-off of inducing Na/K-ATPase-mediated signal transduction leading to cardiac and renal fibrosis, eventually contributing to the development of hypertension and adverse cardiovascular outcomes. In addition, chronic metabolic states resulting in the production of reactive oxygen species (ROS) creating oxidative stress may exacerbate the progression of cardiac and renal disease.