Aldosterone-mediated renal sodium transport requires intact mineralocorticoid receptor DNA binding in the mouse

The classic role of MR is to promote sodium transport in epithelial tissues. However the MR is also expressed in a range of tissues where its role appears unrelated to sodium transport and under normal physiological conditions it may be responding to cortisol (corticosterone in rodents) rather than aldosterone. The relative importance of transcriptional mechanisms such as classical genomic signaling via a hormone response element, transrepression of other transcription factors and non-genomic signaling is not clear, particularly in non-epithelial tissues. The goal of the present study was to define the role of the different signaling pathways for the MR by separating the functional role of classic genomic signaling, mediated by DNA-binding, from these two other mechanisms. We used gene-targeting to generate mice where serine is substituted for cysteine at codon 603 in MR; this mutation precludes DNA-binding. These MR C603S mutant mice die either at birth or fail to thrive, lose weight and die between days 10-13 in a manner similar to that observed previously for mice null for the MR gene. Renal expression and cellular localization of MR C603S by immunohistochemistry was equivalent to control mice. MR C603S mice were rescued by twice daily saline injections. Despite increased aldosterone levels, renal expression of aldosterone-induced genes was not increased. This unique mouse model demonstrates that DNA-binding is essential for the epithelial MR response and will provide the basis for analysis of non-classical signaling of the MR in non-epithelial tissues.