Wilms' tumor protein (-KTS) modulates renin gene transcription.
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.
Steege
Andreas
A
Institut für Physiologie CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Fähling
Michael
M
Paliege
Alexander
A
Bondke
Anja
A
Kirschner
Karin M
KM
Martinka
Peter
P
Kaps
Charlotte
C
Patzak
Andreas
A
Persson
Pontus B
PB
Thiele
Bernd J
BJ
Scholz
Holger
H
Mrowka
Ralf
R
D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025721:WT1 Proteins; D008156:Luciferases; D012083:Renin