Transgenic mouse models to study human mineralocorticoid receptor function in vivo

The mineralocorticoid receptor (MR) is a transcription factor that mediates aldosterone action. MR is expressed in a wide variety of tissues, most notably in sodium-transporting epithelia, but also in nonepithelial cells of the cardiovascular and central nervous systems. However, molecular mechanisms underlying mineralocorticoid signaling and the primary mineralocorticoid-regulated genes are not fully identified. We recently showed that the human MR (hMR) gene possesses two first 5'-untranslated exons 1 alpha and 1 beta, and demonstrated that the 5'-flanking regions of these exons, named P1 and P2, respectively, are functional promoters that differ by their basal and corticosteroid-regulated transcriptional activities. To gain insight into the tissue-specific expression and function of MR, we have established transgenic mouse models using both targeted oncogenesis and receptor overexpression strategies, pi and P2 promoters were used to direct expression of the large T antigen (TAg) of SV40 in constitutively MR-expressing cells. P1.TAg mice developed lethal hibernomas, while P2.TAg animals died from cerebral neuroectodermal tumors and leiomyosarcomas. Quantification of TAg messenger RNA levels revealed that P1 and P2 were differentially utilized. P1 promoter was transcriptionally active in all MR-expressing tissues and importantly directed an appropriate transgene expression in the distal nephron. Conversely, P2 activity was weak and spatially restricted. Several immortalized cell lines were established, thus constituting valuable models to investigate on aldosterone-regulated proteins. We also used P1 and P2 to target overexpression of hMR cDNA in mice. Phenotypic characterization of these mice is currently under investigation. Some transgenic lines should represent useful systems to further explore multiple functions of MR in vivo.