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Rescue of the mineralocorticoid receptor knock-out mouse
M Bleich1, R Warth, M Schmidt-Hieber
1Physiologisches Institut der Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 7, D-79104 Freiburg, Germany.
Abstract:
The mineralocorticoid receptor knock-out mouse (MR-/-), resembling inborn pseudohypoaldosteronism, dies 8-12 days after birth in circulatory failure with all the signs of terminal volume contraction. The present study aimed to examine the functional defects in the kidney and colon in detail and to attempt 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 collecting ducts the amiloride-induced hyperpolarization of the basolateral membrane (Vbl) of nn MR-/- was similar to that of controls, but urinary Na+ excretion was markedly increased to 4.3 micromol/day.g (BW). Based on this measured urinary Na+ loss we tried to rescue nn MR-/- mice by injecting NaCl twice daily (3.85 micromol/g BW), corresponding to 22 microliter of isotonic saline/g BW subcutaneously. This regimen was continued until the animals had reached a body mass of 8.5 g. Thereafter, in addition to normal chow and tap water, NaCl drinking water (333 mmol/l) and pellets soaked in 333 mmol/l NaCl were 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 breeding. When compared to age-matched controls the growth of MR-/- was delayed 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 Vbl in isolated cortical collecting ducts was attenuated. The renin-producing cells were hypertrophic and hyperplastic. Plasma renin and aldosterone concentrations were significantly elevated in MR-/- mice. These data indicate that MR-/- can be rescued by timely and matched NaCl substitutions. This enables the animals to develop through a critical phase of life, after which they adapt their oral salt and water intake to match the elevated excretion rate; however, the renal salt-losing defect persists.
Insights
Mineralocorticoid receptor (MR-/-) mice, mimicking pseudohypoaldosteronism, can be rescued from early death by timely NaCl substitution, allowing survival past a critical phase.
Area of Science:
- Physiology
- Endocrinology
- Nephrology
Background:
- The mineralocorticoid receptor (MR) is crucial for sodium and water balance.
- MR knockout (MR-/-) mice exhibit pseudohypoaldosteronism and die neonatally due to circulatory failure.
- Understanding MR's role in kidney and colon function is vital for treating related disorders.
Purpose of the Study:
- To investigate the functional defects in the kidney and colon of MR knockout mice.
- To determine if neonatal MR knockout mice can be rescued through sodium chloride (NaCl) substitution.
- To analyze the long-term physiological adaptations and persistent defects in rescued MR knockout mice.
Main Methods:
- Comparative analysis of amiloride-sensitive currents in the colon of MR-/- and control mice.
- In vitro perfusion of collecting ducts to assess basolateral membrane potential and urinary Na+ excretion.
- Subcutaneous NaCl injections and oral NaCl supplementation for rescue attempts in neonatal MR-/- mice.
- Monitoring growth, salt/water intake, and renal function in rescued adult MR-/- mice.
Main Results:
- Neonatal MR-/- mice showed reduced colonic current and increased urinary Na+ excretion.
- NaCl substitution therapy enabled survival of MR-/- mice past the critical neonatal period.
- Rescued MR-/- mice exhibited delayed growth initially but normalized later, retaining a persistent Na+-losing defect.
- Elevated plasma renin and aldosterone levels were observed in MR-/- mice, with hypertrophic/hyperplastic renin-producing cells.
Conclusions:
- Timely and matched NaCl substitution is effective in rescuing MR knockout mice from neonatal lethality.
- Rescued MR-/- mice adapt their oral salt and water intake to compensate for persistent renal salt-losing defects.
- This study highlights the critical role of MR in early life and the potential for therapeutic intervention in related conditions.
