2011 Homer Smith Award: To Serve and Protect: Classic and Novel Roles for Na+,K+-Adenosine Triphosphatase

The ability of cells to maintain sharp ion gradients across their membranes is the foundation for the molecular transport and electrical excitability. Across animal species and cell types, Na+,K+-adenosine triphosphatase (ATPase) is arguably the most powerful contributor to this phenomenon. By producing a steep concentration difference of sodium and potassium between the intracellular and extracellular milieu, Na+,K+-ATPase in the tubules provides the driving force for renal sodium reabsorption. Pump activity is downregulated by natriuretic hormones, such as dopamine, and is upregulated by antinatriuretic hormones, such as angiotensin. In the past decade, studies have revealed a novel and surprising role: that Na+,K+-ATPase is a transducer of signals from extracellular to intracellular compartments. The signaling function of Na+,K+-ATPase is activated by ouabain, a mammalian steroid hormone, at far lower concentrations than those that inhibit pump activity. By promoting growth and inhibiting apoptosis, activation of Na+,K+-ATPase exerts tissue-protective effects. Ouabain-stimulated Na+,K+-ATPase signaling has recently shown clinical promise by protecting the malnourished embryonic kidney from adverse developmental programming. A deeper understanding of the tissue-protective role of Na+,K+-ATPase signaling and the regulation of Na+,K+-ATPase pumping activity is of fundamental importance for the understanding and treatment of kidney diseases and kidney-related hypertension.