title: Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism.
abstract: The mineralocorticoid receptor (MR) binds aldosterone and glucocorticoids with equal affinity. In aldosterone target tissues, like the epithelial cells of the distal colon and the principal cells of the collecting ducts in the kidney, the MR is protected from glucocorticoids by the action of the enzyme 11beta-hydroxysteroid-dehydrogenase type 2 (11betaOHSD2), allowing aldosterone to specifically activate the receptor. However, in MR-expressing cells, which lack 11betaOHSD2, like the neurons of the limbic system in the brain, MR is mainly activated by glucocorticoids. MR knockout mice die in the second week after birth, showing at day 8 symptoms of pseudohypoaldosteronism with hyponatremia, hyperkalemia, high renal salt wasting, and a strongly activated renin-angiotensin-aldosterone system (RAAS). The activity of the amiloride-sensitive epithelial Na+ channel (ENaC) is strongly reduced in colon and kidney, but there is no down-regulation of the mRNA abundance of the three ENaC subunits. Daily subcutaneous injections of isotonic NaCl solution until weaning and continued oral NaCl supply lead to survival of the MR knockout mice. The NaCl-rescued MR knockout mice display a strongly enhanced fractional renal excretion of Na+, hyperkalemia, and a persistently strongly activated RAAS. There is almost no renal ENaC activity. The renal mRNA abundance of alphaENaC is reduced by 30%, whereas betaENaC and gammaENaC are not altered.
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Berger
authors.forename: M
authors.initials: M
authors.lastname: Bleich
authors.forename: W
authors.initials: W
authors.lastname: Schmid
authors.forename: R
authors.initials: R
authors.lastname: Greger
authors.forename: G
authors.initials: G
authors.lastname: Schütz
mesh_terms: D000818:Animals; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*
chemical_list: D018161:Receptors, Mineralocorticoid; D012964:Sodium