Rescue of the mineralocorticoid receptor knock-out mouse

The mineralocorticoid receptor knock-out mouse (MR-/-), resembling inborn p seudohypoaldosteronism, dies 8-12 days after birth in circulatory failure w ith all the signs of terminal volume contraction. The present study aimed t o examine the functional defects in the kidney and colon in detail and to a ttempt to rescue these mice. In neonatal (nn) MR-/- the amiloride-sensitive short-circuit current in the colon was reduced to approximately one-third compared to controls (MR+/+ and MR+/-). In isolated in vitro perfused colle cting ducts the amiloride-induced hyperpolarization of the basolateral memb rane (V-bl) of nn MR-/- was similar to that of controls, but urinary Naf ex cretion was markedly increased to 4.3 mu mol/day.g (BW). Based on this meas ured urinary Na+ loss we tried to rescue nn MR-/- mice by injecting NaCl tw ice daily (3.85 mu mol/g BW), corresponding to 22 mu l of isotonic saline/g BW subcutaneously. This regimen was continued until the animals had reache d a body mass of 8.5 g. Thereafter, in addition to normal chow and tap wate r, NaCl drinking water (333 mmol/l) and pellets soaked in 333 mmol/l NaCl w ere offered. Unlike the untreated nn MR-/- most of these mice survived. The adult animals were examined between days 27 and 41, some were used for bre eding. When compared to age-matched controls the growth of MR-/- was delaye d until day 20. Then their growth curve increased in slope and reached that of controls. MR-/- retained their Na+-losing defect. Amiloride's effect on urinary Na+ excretion was not significant in MR-/- mice and the effect on V-bl in isolated cortical collecting ducts was attenuated. The renin-produc ing cells were hypertrophic and hyperplastic. Plasma renin and aldosterone concentrations were significantly elevated in MR-/- mice. These data indica te that MR-/- can be rescued by timely and matched NaCl substitutions. This enables the animals to develop through a critical phase of life, after whi ch they adapt their oral salt and water intake to match the elevated excret ion rate; however, the renal salt-losing defect persists.