title: Enhanced expression of epithelial sodium channels causes salt-induced hypertension in mice through inhibition of the α2-isoform of Na+, K+-ATPase.
abstract: Knockout of the Nedd4-2 gene in mice results in overexpression of epithelial sodium channels (ENaC) on the plasma membrane in the kidney, choroid plexus and brain nuclei. These mice exhibit enhanced pressor responses to CSF [Na(+)] as well as 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 ouabain-resistant α2R/R-isoform of Na(+), K(+)-ATPase. Intracerebroventricular (icv) infusion of Na(+)-rich aCSF (225 mmol/L 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. Icv infusion of EO-binding Fab fragments also blocked the BP response in Nedd4-2(-/-) mice. In Nedd4-2(-/-) mice, 8% high-salt diet increased MAP by 25-30 mmHg, but in α2R/R/Nedd4-2(-/-) mice, it increased by only 5-10 mmHg. In contrast, Nedd4-2(-/-) or α2R/R did not affect the hypertension caused by sc infusion of Ang II. 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.
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Ontario, Canada fleenen@ottawaheart.ca.
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Hou
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Monir
authors.initials: M
authors.lastname: Ahmad
keywords: Angiotensin II; Liddle syndrome; brain; endogenous ouabain