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Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism
1Division of Molecular Biology of the Cell I, German Cancer Research Centre, Heidelberg, Germany.
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.
Insights
Mineralocorticoid receptor (MR) knockout mice exhibit pseudohypoaldosteronism and die shortly after birth. Survival is achieved with NaCl supplementation, revealing persistent MR dysfunction and reduced epithelial sodium channel (ENaC) activity.
Area of Science:
- Endocrinology
- Molecular Biology
- Physiology
Background:
- The mineralocorticoid receptor (MR) binds both aldosterone and glucocorticoids.
- In specific tissues, 11beta-hydroxysteroid dehydrogenase type 2 (11betaOHSD2) protects MR from glucocorticoids, enabling aldosterone specificity.
- MR-expressing cells lacking 11betaOHSD2 are primarily activated by glucocorticoids.
Purpose of the Study:
- To investigate the physiological role of the mineralocorticoid receptor (MR).
- To characterize the phenotype of MR knockout mice and the effects of NaCl supplementation.
Main Methods:
- Generation and analysis of MR knockout mice.
- Phenotypic characterization including electrolyte balance, renin-angiotensin-aldosterone system (RAAS) activity, and epithelial sodium channel (ENaC) function.
- Assessment of ENaC subunit mRNA abundance in NaCl-rescued MR knockout mice.
Main Results:
- MR knockout mice exhibit pseudohypoaldosteronism with hyponatremia, hyperkalemia, salt wasting, and activated RAAS, leading to early mortality.
- NaCl supplementation rescues MR knockout mice, but they retain hyperkalemia, activated RAAS, and significantly reduced renal ENaC activity.
- Reduced alphaENaC mRNA abundance was observed in NaCl-rescued MR knockout mice, while betaENaC and gammaENaC remained unchanged.
Conclusions:
- The mineralocorticoid receptor is essential for survival and proper sodium homeostasis.
- MR signaling is critical for regulating epithelial sodium channel (ENaC) activity in the kidney and colon.
- NaCl supplementation can prevent lethality in MR deficiency but does not fully restore ENaC function or electrolyte balance.