Transgenic mouse models to study human mineralocorticoid receptor functionin vivo

The mineralocorticoid receptor (MR) is a transcription factor that mediates aldosterone action. MR is expressed in a wide variety of tissues, most not ably in sodium-transporting epithelia, but also in nonepithelial cells of t he cardiovascular and central nervous systems. However, molecular mechanism s 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 an d 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 tran sgenic mouse models using both targeted oncogenesis and receptor overexpres sion 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 promot er was transcriptionally active in all MR-expressing tissues and importantl y directed an appropriate transgene expression in the distal nephron. Conve rsely, P2 activity was weak and spatially restricted. Several immortalized cell lines were established, thus constituting valuable models to investiga te on aldosterone-regulated proteins. We also used P1 and P2 to target over expression of hMR cDNA in mice. Phenotypic characterization of these mice i s currently under investigation. Some transgenic lines should represent use ful systems to further explore multiple functions of MR in vivo.