Inactivation of the mineralocorticoid receptor (MR) gene in the germline results in salt wasting and early postnatal lethality. To determine the role of kidney collecting duct principal cells in aldosterone-driven Na+ reabsorption, mice were generated using the Cre-loxP recombination system. Cre expression was driven by the aquaporin 2 gene. Mutant mice were defective for MR downstream the early connecting tubule. They showed a dramatic increase in plasma aldosterone concentration but still were able to compensate for Na+ loss unless challenged by dietary Na+ depletion. The major site of renal compensation was the renal distal convoluted tubule and early connecting tubule. Another site of Na+ conservation was the distal colon. We determined the amiloride (50mmol/l) inhibitable transepithelial Na + transport by rectal potential difference (rPD) and Ussing chamber measurements (n=4-7). Under control diet amiloride changed rPD by 9±0,5mV in controls and by 17±1,6mV in mutants. The corresponding aldosterone concentrations were 450 and 4954pg/ml. After a 10 day Na+ restriction aldosterone increased in controls to 3167pg/ml and even further in mutants to 19719pg/ml. The corresponding rPD changes were 22±4,7mV in controls and 35±4mV in mutants. The equivalent short circuit currents under these conditions were 648±187mA/cm 2 and 1330±97mA/cm 2, respectively.

Conclusion: Kidney and colon show a large range of compensation in conditions of Na+ loss.