We examined the modulating effects of the (-KTS) splice form of the Wilms' tumor protein (WT1) on renin expression through transcriptional control. We show that WT1(-KTS) interacts with a regulatory region (hRENc) ~12 kb upstream of the renin promoter, and has a suppressing influence on renin gene transcription. Initial bioinformatical prediction of a WT1 binding site was confirmed by reporter gene assays, and gel shift approaches. Co-expression of WT1 and Renin was observed in the AS4.1 cell line which is derived from renin producing juxtaglomerular cells. Furthermore, we demonstrate that WT1(- KTS) over-expression in stable transfected HEK293 cells, as well as in transiently transfected cells decreased renin mRNA and protein levels. The insertion of a mutation in the WT1(-KTS) protein, which is associated with the formation of Wilms' tumor, failed to suppress the reporter gene activity and endogenous renin mRNA, consequently leading to accumulation of renin. These findings indicate that the renin gene transcription is modulated by WT1(-KTS). Our data provide an explanation for clinical findings, showing a hyperreninism in patients suffering from mutations in the WT1 gene.