Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor

The mineralocorticoid receptor (MR), a ligand-dependent transcription facto r, mediates aldosterone actions in a large variety of tissues. To explore t he functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive express ion of hMR in aldosterone target tissues. Tissue-specific analysis of trans gene expression in two independent transgenic animal (TG) lines by ribonucl ease protection assays revealed that hMR is expressed in all mineralocortic oid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose pr evalence increased with aging. Renal clearance studies also disclosed a sig nificant decrease in urinary potassium excretion rate in TG. hMR-expressing animals had normal blood pressure but developed mild dilated cardiomyopath y (increased left ventricle diameters and decreased shortening fraction), w hich was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2- to 5-fold increase in cardiac expres sion of atrial natriuretic peptide, serum- and glucocorticoid-induced kinas e, and early growth response gene 1 as detected by microarrays; renal serum - and glucocorticoid-induced kinase was also induced significantly. Altoget her, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the ti ssue-specific mineralocorticoid signaling pathways.