Increased Renin Production in Mice With Deletion of Peroxisome Proliferator-Activated Receptor-γ in Juxtaglomerular Cells

Abstract

We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)γ stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARγ. The mouse renin gene is regulated by PPARγ through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARγ knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARγ would upregulate mouse renin expression. Consistent with these observations knockdown of PPARγ increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARγ on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPARγ locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARγ fl/fl mice). We provide evidence that PPARγ expression was effectively reduced in JG cells of RC-PPARγ fl/fl mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARγ fl/fl than in littermate control RC-PPARγ wt/wt mice. Renin mRNA levels and plasma renin concentration in RC-PPARγ 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-PPARγ wt/wt and RC-PPARγ fl/fl mice. These data demonstrate that the JG-specific PPARγ deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARγ appears to be a relevant transcription factor for the control of renin gene in JG cells.