The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone. Generation of tissue-selective MR-deficient mice using the Cre recombinase-LoxP gene targeting system made possible mice lacking MR only in specific cell types. Targeting renal-specific MR differentiated roles in specific compartments of the kidney. Ablating MR in neurons of the forebrain reinforced important roles of the MR in responses to stress, behaviour and anxiety, but suggested a minimal role in maintaining basal HPA axis tone. Deletion of the MR in macrophages and other cell-types of the cardiovascular system clearly defined important roles for the regulation of cardiovascular physiology and pathophysiology. Knockdown of MR mRNA in vivo using antisense/siRNA approaches, and similarly MR overexpression, have provided useful rodent models to study physiological roles of MR signalling in vivo. More recently targeted mutation of specific domains of the MR such as the DBD has defined genomic versus non-genomic roles in vivo. New tissue-selective MR-null models are required to define roles of MR signalling in other regions of the brain, the eye, gastrointestinal tract, lung, skin, breast and gonadal organs
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