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.

Identification of a VxP Targeting Signal in the Flagellar Na+/K+‐ATPase

“…GFP‐α3 /α4 and GFP‐α4 /α3, were localized in patterns opposite to that of the parent constructs demonstrating that the targeting information lies within the intrinsically disordered region (Figure A,B). A subsequent pair of chimeras with only 24 amino acids substituted, GFP‐α3 /α4 and GFP‐α4 /α3, was generated and found to also have reversed localization patterns compared with the parent constructs (Figure C,D). A final pair of chimeras, GFP‐α3 /α4 and GFP‐α4 /α3, revealed that the amino acid motif responsible for differential localization was contained within the first 14 amino acids (Figure E,F).…”

“…A subsequent pair of chimeras with only 24 amino acids substituted, GFP‐α3 /α4 and GFP‐α4 /α3, was generated and found to also have reversed localization patterns compared with the parent constructs (Figure C,D). A final pair of chimeras, GFP‐α3 /α4 and GFP‐α4 /α3, revealed that the amino acid motif responsible for differential localization was contained within the first 14 amino acids (Figure E,F).…”

Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure

“…CTS confer a conformational change to the Na/K-ATPase that releases the Src kinase domain, thus activating Src kinase and multiple downstream targets 2, 8, 11 . This novel Na/K-ATPase-mediated signaling is responsible for a variety of key cellular roles involving cell growth/hypertrophy, reactive oxygen species production, and collagen synthesis 6 .…”

“…This serves to remove the Na/K-ATPase from the basolateral membrane and thus reduces the transport of sodium from the tubular lumen to the blood compartment, thereby increasing sodium excretion 6, 7 . However, CTS may exert “off-target” signal transduction effects beyond their direct effects on the sodium pump 2, 8 . Hence, chronic stimulation of Na/K-ATPase signaling by CTS has important implications for not only for the natriuretic response to increased salt load 9 but also has been implicated in pathological adaptation to volume expansion including hypertension, hypertrophy, and fibrosis 10, 11 .…”

Endogenous Cardiotonic Steroids in Kidney Failure: A Review and an Hypothesis

“…In the scheme presented, sustained increases in MBG and EO elevate BP and also promote renal and cardiac damage that enhances the progression of renal failure. The signaling pathways for the fibrotic effects have been described elsewhere 41,91 . This feed-forward mechanism provides further stimulus to circulating EO and MBG and may accelerate progression to complete failure.…”