Abstract 530: Enhanced Expression Of Epithelial Sodium Channels (ENaC) Causes Salt-induced Hypertension In Mice Through Inhibition Of The α2-isoform Of Na+, K+-atpase
Knockout of the Nedd4-2 gene in mice results in overexpression of ENaC on the plasma membrane in kidneys, choroid plexus and brain nuclei. These mice exhibit enhanced pressor responses to CSF [Na+] and dietary salt-induced hypertension which both can be blocked by central infusion of the ENaC blocker benzamil. Functional studies suggest that ENaC activation in the CNS results in release of endogenous ouabain (EO) and inhibition of the α2-isoform of Na+, K+-ATPase. To test this concept more specifically, we studied Nedd4-2-/- mice expressing the α2R/R-isoform of Na+, K+-ATPase. Intracerebroventricular (icv) infusion of Na+-rich aCSF (225 mM Na+ at 0.4 μl/min) increased MAP by 10-15 mmHg in wild type mice and by 25-30 mmHg in Nedd4-2-/- mice, but by only ~5 mmHg in α2R/R and in α2R/R/Nedd4-2-/- mice (Fig top panel). Icv infusion of EO-binding Fab fragments also blocked the BP response in Nedd4-2-/- mice. In Nedd4-2-/- mice high salt diet increased MAP by 25-30 mmHg, but in α2R/R/Nedd4-2-/- mice by only 5 mmHg (Fig bottom panel). These findings substantiate the concept that enhanced ENaC activity causes salt-induced pressor responses mainly through EO inhibiting the α2-isoform of Na+, K+-ATPase in the brain.
Author Disclosures: F. Leenen: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; CIHR. X. Hou: None. H. Wang: None.
- © 2014 by American Heart Association, Inc.