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

Fatimah K Khalaf, Prabhatchandra Dube, Amal Mohamed, Jiang Tian, Deepak Malhotra, Steven T Haller, David J Kennedy, Fatimah K Khalaf, Prabhatchandra Dube, Amal Mohamed, Jiang Tian, Deepak Malhotra, Steven T Haller, David J Kennedy

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.

Keywords: Na+/K+-ATPase; cardiotonic steroids; fibrosis; inflammation; signaling.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustrating the role of the CTS-NKA-Src (cardiotonic steroids- Na+/K+-ATPase-Src kinase) signaling axis in both its physiologic natriuretic role as well as the trade-off effects induced through stimulation of cardiac, renal, and vascular cell types.
Figure 2
Figure 2
Summary of the known proinflammatory and profibrotic signaling mechanisms mediated by the CTS-NKA-Src signaling axis in cardiac [44,63,73,74,75,76,77,78,80,81,82], renal [32,39,43,51,52,55,63,64,65]], vascular [69,70,92], adipocyte [93,94,95,96,97,98,99,100,101,102,103,104,105], and immune cells [16,56].
Figure 3
Figure 3
Summary of novel signaling interactions identified between the NKA and other cell surface receptors in renal epithelial and immune cell types [14,24,56,132,133,134,135,136,137,138,139,140,141,142,143].

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