Mineralocorticoid receptor knockout mice: Lessons on Na+ metabolism

• Published in: Kidney international Vol. 57; no. 4; pp. 1295 - 1298
• Main Authors: Berger, Stefan, Bleich, Markus, Schmid, Wolfgang, Greger, Rainer, Schütz, Günther
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2000; Nature Publishing; Elsevier Limited
• Subjects: aldosterone; amiloride; Animals; Biological and medical sciences; Cell receptors; Cell structures and functions; Fundamental and applied biological sciences. Psychology; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; knockout animals; Mice; Mice, Knockout - genetics; Molecular and cellular biology; receptor; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - physiology; sodium; Sodium - metabolism; sodium; amiloride; knockout animals; receptor; aldosterone; Mineralocorticoid; Rodentia; Ion transport; Exploration; Receiver; Aldosterone; Metabolism; Vertebrata; Mammalia; Sodium; Mouse; Animal; Death
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1046/j.1523-1755.2000.00965.x

Mineralocorticoid receptor knockout mice: Lessons on Na+ metabolism. 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 11β-hydroxysteroid-dehydrogenase type 2 (11βOHSD2), allowing aldosterone to specifically activate the receptor. However, in MR-expressing cells, which lack 11βOHSD2, 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 αENaC is reduced by 30%, whereas βENaC and γENaC are not altered.