Inhibition of the Signaling Function of Na/K‐ATPase Produces Salt‐Sensitive Hypertension

Abstract

We have previously shown that the Na/K‐ATPase (NKA) acts as a receptor for cardiotonic steroids such as ouabain and salt to regulate Src kinase activities (Tian et al., Mol Biol Cell, 2006, 17:317; Ye et al., JBC, 2011). Here, we test the physiological role of this newly discovered signaling mechanism. Activation of NKA signaling by ouabain leads to endocytosis of both NKA and NHE3, which causes a reduction of transcellular Na+ transport in LLC‐PK1 cell monolayer. Expression of the N‐terminus of NKA α1 subunit (NT), which functions as a dominant negative mutant, specifically blocks the NKA signaling and prevents ouabain‐induced inhibition of transcellular Na+ transport. These in vitro experiments suggest that the signaling NKA be involved in the regulation of renal sodium handling and therefore, may play a role in the control of blood pressure (BP). To test this hypothesis in vivo, we have generated NT‐YFP transgenic mice (NT mice) and measured BP after mice were fed with either normal (0.5% NaCl) or high salt diet (4.0%). The high salt diet increased BP from 110 mmHg to 160 mmHg in NT mice, but not in age‐matched littermates. Moreover, renal functional curves reveal a salt‐sensitive hypertension phenotype in NT mice.