Increased Renin Production in Mice With Deletion of Peroxisome Proliferator-Activated Receptor-γ 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 PPAR gamma. The mouse renin gene is regulated by PPAR gamma through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPAR gamma knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPAR gamma would upregulate mouse renin expression. Consistent with these observations knockdown of PPAR gamma increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPAR gamma on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPAR gamma locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPAR gamma(fl/fl) mice). We provide evidence that PPAR gamma expression was effectively reduced in JG cells of RC-PPAR gamma(fl/fl) mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPAR gamma(fl/fl) than in littermate control RC-PPAR gamma(wt/wt) mice. Renin mRNA levels and plasma renin concentration in RC-PPAR gamma(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-PPAR gamma(wt/wt) and RC-PPAR gamma(fl/fl) mice. These data demonstrate that the JG-specific PPAR gamma deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPAR gamma appears to be a relevant transcription factor for the control of renin gene in JG cells. (Hypertension. 2010; 55: 660-666.)