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 pse udohypoaldosteronism. They finally lost weight and eventually died at around day 10 after birth from dehydration by renal sodium and water l oss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a stron g increase in renin, angiotensin II, and aldosterone plasma concentrat ions, Methods were established to measure renal clearance and colonic transepithelial Na+ reabsorption in 8-day-old mice in vivo. The fracti onal renal Na+ excretion was elevated >8-fold. The glomerular filtrati on rate in -/- mice was not different from controls. The effect of ami loride on renal Na+ excretion and colonic transepithelial voltage refl ects the function of amiloide-sensitive epithelial Na+ channels (ENaC) . In -/- mice, it was reduced to 24% in the kidney and to 16% in the c olon, There was, however, still significant residual ENaC-mediated Na reabsorption in bath epithelia. RNase protection analysis of the subu nits of ENaC and (Na+ + K+)-ATPase did not reveal a decrease in -/- mi ce. The present data indicate that MR-deficient neonates die because t hey are not able to compensate renal Na+ loss. Regulation of Na+ reabs orption via MR is not achieved by transcriptional control of ENaC and (Na+ + K+)-ATPase in RNA abundance but by transcriptional control of o ther as yet unidentified genes. MR knockout mice will be a suitable to ol far the search of these genes.