1. ¹Institut für Physiologie CCM, Charité––Universitätsmedizin Berlin, Berlin, Germany
2. ²Institut für Biologie, Freie Universität Berlin, Berlin, Germany
3. ³Institut für Vegetative Anatomie, Charité––Universitätsmedizin Berlin, Berlin, Germany
4. ⁴Institut für Physiologie CCM, AG Systems Biology––Computational Physiology, Charité––Universitätsmedizin Berlin, Berlin, Germany

Correspondence: Ralf Mrowka, Institut für Physiologie CCM, AG Systems Biology––Computational Physiology, Charité––Universitätsmedizin Berlin, Tucholskystrasse 2, Berlin D-10117, Germany. E-mail: ralf.mrowka@charite.de

Received 24 November 2006; Revised 28 February 2008; Accepted 4 March 2008; Published online 21 May 2008.

Abstract

Renin plays a crucial role in the control of various physiological processes such as blood pressure and body fluid homeostasis. Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription. Using bioinformatics tools, we initially predicted that a WT1-binding site exists in a regulatory region about 12 kb upstream of the renin promoter; this was confirmed by reporter gene assays and gel shift experiments in heterologous cells. Co-expression of Wt1 and renin proteins was found in rat kidney sections, mouse kidney blood vessels, and a cell line derived from the juxtaglomerular apparatus that produces renin. Knockdown of WT1 protein by siRNA significantly increased the cellular renin mRNA content, while overexpression of WT1(-KTS) reduced renin gene expression in stable and transiently transfected cells. A mutant WT1(-KTS) protein found in Wilms' tumors failed to suppress renin gene reporter activity and endogenous renin expression. Our findings show that renin gene transcription is regulated by the WT1(-KTS) protein and this may explain findings in patients with WT1 gene mutations of increased plasma renin and hypertension.