Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells.
We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse renin gene is regulated by PPARgamma through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARgamma knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARgamma would upregulate mouse renin expression. Consistent with these observations knockdown of PPARgamma increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARgamma on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPARgamma locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARgamma(fl/fl) mice). We provide evidence that PPARgamma expression was effectively reduced in JG cells of RC-PPARgamma(fl/fl) mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARgamma(fl/fl) than in littermate control RC-PPARgamma(wt/wt) mice. Renin mRNA levels and plasma renin concentration in RC-PPARgamma(fl/fl) mice were almost 2-fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARgamma(wt/wt) and RC-PPARgamma(fl/fl) mice. These data demonstrate that the JG-specific PPARgamma deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARgamma appears to be a relevant transcription factor for the control of renin gene in JG cells.
Desch
Michael
M
Institute of Physiology, University of Regensburg, D-93040 Regensburg, Germany.
Schreiber
Andrea
A
Schweda
Frank
F
Madsen
Kirsten
K
Friis
Ulla G
UG
Weatherford
Eric T
ET
Sigmund
Curt D
CD
Sequeira Lopez
Maria Luisa
ML
Gomez
R Ariel
RA
Todorov
Vladimir T
VT
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D006400:Hematocrit; D006801:Humans; D019426:Integrases / Q000235:genetics; D007606:Juxtaglomerular Apparatus / Q000502:physiology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000097:blood* / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D047495:PPAR gamma; D012333:RNA, Messenger; D008156:Luciferases; C045073:Cre recombinase; D019426:Integrases; D012083:Renin