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.