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

本项目旨在研究核受体PPARgamma在肾素基因转录调控中的作用。我们已经描述了PPARgamma参与调节肾素表达，并且人肾素基因具有称为Pal 3的独特PPARgamma结合序列。Pal 3基序介导了一个更强的反式激活的人肾素基因相比，小鼠的肾素基因。因此，人的肾素Pal 3网站将进一步在体外通过研究其转录因子的结合功能，以及在天然和永生化的克隆肾素生产细胞的核受体的表达模式。接下来，将研究Pal 3序列在体内控制人肾素基因表达中的作用。为此，将通过转基因共放置产生具有野生型或突变的Pal 3的两个人源化小鼠系。最后，PPARgamma与肥胖时肾素过度产生和动脉高血压发展的相关性将被阐明。为此，将使用在产生肾素的细胞中具有PPARgamma缺陷的小鼠作为模型。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。这一知识是临床相关的，因为它将有助于全面了解肾素-血管紧张素系统，从而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.