PPARs in CYP450 Dependent Regulation of Kidney Function

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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.