Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism.
Mineralocorticoid receptor (MR)-deficient mice were generated by gene targeting. These animals had a normal prenatal development. During the first week of life, MR-deficient (-/-) mice developed symptoms of pseudohypoaldosteronism. They finally lost weight and eventually died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations. Methods were established to measure renal clearance and colonic transepithelial Na+ reabsorption in 8-day-old mice in vivo. The fractional renal Na+ excretion was elevated >8-fold. The glomerular filtration rate in -/- mice was not different from controls. The effect of amiloride on renal Na+ excretion and colonic transepithelial voltage reflects the function of amiloide-sensitive epithelial Na+ channels (ENaC). In -/- mice, it was reduced to 24% in the kidney and to 16% in the colon. There was, however, still significant residual ENaC-mediated Na+ reabsorption in both epithelia. RNase protection analysis of the subunits of ENaC and (Na++ K+)-ATPase did not reveal a decrease in -/- mice. The present data indicate that MR-deficient neonates die because they are not able to compensate renal Na+ loss. Regulation of Na+ reabsorption via MR is not achieved by transcriptional control of ENaC and (Na+ + K+)-ATPase in RNA abundance but by transcriptional control of other as yet unidentified genes. MR knockout mice will be a suitable tool for the search of these genes.
Division Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
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S
Berger
M
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Bleich
W
W
Schmid
T J
TJ
Cole
J
J
Peters
H
H
Watanabe
W
W
Kriz
R
R
Warth
R
R
Greger
G
G
Schütz
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001834:Body Water; D017931:DNA Primers; D051379:Mice; D018345:Mice, Knockout; D009318:Natriuresis / Q000235:genetics; D011546:Pseudohypoaldosteronism / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics
D017931:DNA Primers; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D000584:Amiloride; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase