Ouabain-Sensitive α1 Na,K-ATPase Enhances Natriuretic Response to Saline Load

Abstract

Na,K-ATPase is ubiquitously expressed and is essential for maintaining electrochemical and osmotic gradients. The alpha subunit of Na,K-ATPase is the receptor for cardiotonic steroids, which act through the ouabain-binding site and are important in cardiovascular regulation. Interestingly, the presence of endogenous Na,K-ATPase ligands has been implicated in the natriuretic response to perturbations such as hypertension and salt loading; therefore, it is important to characterize the role of the ouabain-binding sites in this context. Because the alpha1 isoform of mice and rats is relatively ouabain resistant, gene-targeting strategies were used to produce mice with reversed responses of the alpha1 and/or alpha2 isoforms to ouabain to assess for altered natriuretic responses to acute salt loading. Regardless of the sensitivity of the alpha2 isoform to ouabain, conferring ouabain sensitivity to alpha1 augmented the natriuretic response to an acute salt load. In addition, when endogenous Na,K-ATPase inhibitors were sequestered with an anti-digoxin antibody fragment, the sodium excretion rates in the ouabain-sensitive alpha1 isoform mice were equivalent to the ouabain-resistant alpha1 isoform mice. These data suggest that the ouabain-binding site of the alpha1 Na,K-ATPase can participate in the natriuretic response to a salt load by responding to endogenous Na,K-ATPase ligands.

Impairment of Na/K-ATPase Signaling in Renal Proximal Tubule Contributes to Dahl Salt-sensitive Hypertension

“…While volume expansion is considered to be the main cause of the salt-sensitive hypertension in the S rats (2,20), accumulating evidence, some from our laboratories, suggest that endogenous CTS regulate renal Na ϩ handling and BP through the Na/K-ATPase signaling (5,6,(21)(22)(23)(24)(25)(26). A role for endogenous CTS in salt sensitive hypertension has also been suggested by a number of authors (10,(27)(28)(29).…”

Involvement of Reactive Oxygen Species in a Feed-forward Mechanism of Na/K-ATPase-mediated Signaling Transduction

“…These include transgenic mice with a "humanized" ouabain-sensitive Na/K-ATPase ␣1 subunit, CTS infusion, and immunoneutralization of endogenous CTS (12,22,(37)(38)(39)(40). For many years, the concept of CTS elimination of excessive sodium by direct inhibition of Na/KATPase has been a topic of debate.…”

Identification of a Mutant α1 Na/K-ATPase That Pumps but Is Defective in Signal Transduction

“…Although their pathophysiological significance has been a subject of debate for many years (29), several gene replacement studies from Lingrel and co-workers (30,31) have unequivocally demonstrated an important role of endogenous CTS in regulation of renal Na ϩ excretion and blood pressure. In addition, we and others showed that CTS not only induced hypertension in rats but also caused significant cardiovascular remodeling independent of their effect on blood pressure (5,20,31,32). Moreover, CTS may play an important role in embryonic development (19).…”

“…To this end, we know that the Src pathway is activated by high salt intake and by infusion of physiologically relevant amount of CTS (5). Thus, ␣1 gene replacement using the newly identified A420P mutant would allow us to conduct experiments similar to those carried out by Lingrel and co-workers (30,31) to assess specifically the Src regulatory function of Na/K-ATPase in renal salt handling, organ remodeling, and embryonic development.…”