Expression and function of the human mineralocorticoid receptor: lessons from transgenic mouse models

Abstract

The human mineralocorticoid receptor (hMR), a ligand-dependent transcription factor (NR3C2) which belongs to the nuclear receptor superfamily, mediates most of the known effects of aldosterone. Beside its involvement in the regulation of sodium balance and the control of blood pressure, aldosterone-hMR tandem also exerts important regulatory functions on the cardiovascular and central nervous systems. To study the molecular mechanisms involved in the tissue-specific expression of hMR and explore its functional implication in pathophysiology, transgenic mouse models have been generated using both targeted oncogenesis and MR overexpression. We have previously demonstrated that the transcription of hMR is directed by two alternative promoters, P1 and P2, which correspond to the 5'-flanking regions of the untranslated exons 1alpha and 1beta of the hMR gene, respectively. Utilization of P1 and P2 to drive expression of the SV40 large T antigen (TAg) in transgenic mice led us (i) to determine distinct tissue-specific patterns of promoter usage; (ii) to identify novel sites of MR expression including brown adipose tissue, thus providing a new functional link between aldosterone and energy homeostasis; (iii) to generate original immortalized cell lines derived from numerous aldosterone-sensitive tissues most notably distal nephron, brown fat, skin, liver, lung, brain, heart, blood vessels and inner ear. These differentiated cell lines represent suitable models to further explore cell-specific mineralocorticoid responses and cross-talk with other signaling pathways. Generation of transgenic mice in which hMR expression was directed by P1 promoter demonstrated the importance of MR in the cardiac and renal function. Morphological and functional alterations of the renal tubule were observed with basal decreased sodium/potassium ratio exacerbated under sodium depletion. Hypokinetic dilated cardiomyopathies were associated with tachycardia, arrhythmia but normal arterial blood pressure emphasizing the direct role of MR on cardiomyocyte function. Taken together, transgenic animal models constitute valuable experimental systems to gain new insights into the widespread and pleiotropic in vivo functions of MR.