Role of PPARgamma in the regulation of renin gene expression: from molecule to organism

本项目旨在探讨核受体PPARgamma在肾素基因转录调控中的作用。我们已经描述了PPARgamma参与肾素表达的调控，并且人类肾素基因具有独特的PPARgamma结合序列，称为Pal3。与小鼠肾素基因相比，Pal3基序介导的人肾素基因的反激活更强。因此，在体外进一步研究人肾素Pal3位点的转录因子结合特征以及核受体在原生和永活克隆肾素产生细胞中的表达模式。接下来，我们将研究Pal3序列在体内控制人肾素基因表达中的作用。为此，将通过转基因共植入产生两种具有野生型或突变Pal3的人源化小鼠系。最后，本文将阐明PPARgamma与肥胖期间肾素过量产生和动脉高血压发展的相关性。为此，将肾素生成细胞中PPARgamma缺乏的小鼠作为模型。我们期望从这些实验中获得关于控制肾素表达的细胞内机制的新数据。这些知识具有临床相关性，因为它将有助于全面了解肾素-血管紧张素系统，从而了解动脉高血压的分子机制。

This project aims to investigate the role of nuclear receptor PPARgamma in the transcriptional control of the renin gene. We have described that PPARgamma is involved in the regulation of renin expression and that the human renin gene has a unique PPARgamma binding sequence termed Pal3. The Pal3 motif mediates a stronger transactivation of the human renin gene in comparison with the mouse renin gene. Therefore the human renin Pal3 site will be further characterized in vitro by studying its transcription factor-binding features as well as the expression pattern of nuclear receptors in native and immortalized clonal renin-producing cells. Next, the role of the Pal3 sequence in the control of the human renin gene expression in vivo will be investigated. To this end, two humanized mouse lines with wild-type or mutated Pal3 will be generated by transgene co-placement. At last, the relevance of PPARgamma for the renin overproduction and the development of arterial hypertension during obesity will be elucidated. For this purpose, mice with PPARgamma deficiency in the reninproducing cells will be used as model. We expect from these experiments novel data regarding the intracellular machinery which controls renin expression. This knowledge is clinically relevant because it will contribute to the overall understanding of the renin-angiotensin-system and thus of the molecular mechanisms of arterial hypertension.