PPARs in CYP450 Dependent Regulation of Kidney Function

在缺乏细胞色素P450 4a 14的小鼠中证明高血压提供了明确的证据。 CYP 450系统与血压控制相关的证据。尽管其他证据表明细胞色素P450衍生的花生四烯酸代谢物（CYP 450-AA代谢物）介导肾脏微血管效应和对肾脏盐吸收的效应，但CYP 450-AA代谢物的分子靶点的鉴定仍然难以捉摸。核受体（包括盐皮质激素和雄激素受体）的激活异常是人类高血压的公认原因，最近发现另一类核受体过氧化物酶体增殖物激活受体（PPARs）的突变也可导致人类高血压。PPARs还显示既可转录调节CYP 450的表达，也可结合CYP 450 AA代谢物并被其激活。本项目的目的是检验以下假设：PPARgamma不仅是CYP 450 AA代谢物的关键靶点，介导该家族化合物的上皮和微血管效应，而且还调节CYP 450表氧化酶的表达。 具体目标1中拟定的研究：将使用Cre/Lox系统从小鼠集合管和其他肾单位节段中条件性删除“floxed”PPARgamma等位基因，检查CYP 450和PPARgamma在调节肾上皮离子转运中的相互作用。 还将研究CYP 450衍生的花生四烯酸代谢物作为PPARgamma配体的潜力。具体目标2将检查PPARgamma在调节CYP 450 AA表氧化酶产物（Ehrs）和DHEhrs在调节血管张力和血压中的作用。 通过这些研究，我们希望建立一个新的分子途径，有助于通过CYP 450调节血压。

The demonstration of hypertension in mice lacking Cytochrome P450 4a14 provides unequivocal evidence linking the CYP450 system with blood pressure control. Although other evidence implicates Cytochrome P450 derived arachidonate metabolites (CYP450-AA metabolites) as mediating both renal microvascular effects and effects on renal salt absorption, identification of a molecular target of CYP450-AA metabolites has remained elusive. Abnormalities in activation of nuclear receptors including mineralocorticoid and androgen receptors are well-established causes of hypertension in man. More recently mutations in another group of nuclear receptors, the peroxisome proliferator activated receptors (PPARs), have also been found to result in human hypertension. PPARs have also been shown both to transcriptionally modulate the expression of CYP450s and also bind and be activated by CYP450 AA metabolites. This goal of this project is to test the hypothesis that PPARgamma are not only key target of CYP450 AA metabolites, mediating both the epithelial and microvascular effects of this family of compounds, but also modulate the expression of CYP450 epoxygenases. The studies proposed in Specific aim 1: will examine the interaction between CYP450s and PPARgamma in regulating renal epithelial ion transport, using the Cre/Lox system to conditionally delete a "floxed" PPARgamma allele from the mouse collecting duct and other nephron segments. The potential of CYP450 derived arachidonate metabolites as PPARgamma ligands will also be studied. Specific Aim 2 will examine the role PPARgamma in modulating CYP450 AA epoxygenase products (EETs) and DHETs in modulating vascular tone and blood pressure. Through these studies we hope to establish a novel molecular pathway contributing to the regulation of blood pressure by CYP450s.