Currently, gene disruption by homologous recombination in embryonic stem cells is only feasible in mice. To circumvent this problem, we silenced mineralocorticoid receptor (MR) expression by RNA interference in knockdown rats generated through lentiviral transgenesis. Analysis of the F1 progeny at 3 wk of age revealed strongly decreased MR levels. This was specific for the targeted gene and related to the abundance of the short interfering RNA. Reminiscent of MR knockout mice, the transgenic rats showed a reduced body weight, elevated serum aldosterone levels, increased plasma renin activity, and altered expression of MR target genes. Some of these effects correlated with the degree to which MR mRNA expression was reduced. Whereas disruption of the MR by gene targeting in mice leads to postnatal death, our strategy also allowed obtaining adult knockdown rats with defects in hormone and electrolyte homeostasis resembling pseudohypoaldosteronism. In conclusion, this is the first example of a human disease model based on RNA interference in rats.