Human Hypertension and P450 Co-Hydroxylases and Epoxygenases

肾脏在控制体液容量和成分以及肾小管和/或 血流动力学障碍是高血压和糖尿病等疾病的常见特征。肾脏 P450花生四烯酸(AA)单加氧酶生物合成羟基和环氧AA衍生物，这些衍生物 已知可调节肾小管运输和血管反应性。P450基因功能障碍的动物模型 确认了这些酶的生理重要性，表征了它们的病理生理作用，以及 提供了对其代谢物的作用机制的见解。血管紧张素转换酶的病理生理作用研究 人类P450发现P450基因变异与高血压、高血压进展 肾脏疾病，并与代谢综合征的组成部分。此应用程序建议在这些基础上构建 研究和解决：a)P450-二十烷类化合物调节肾小管运输和 血管反应性，b)P450在人类高血压和糖尿病肾脏并发症中的作用，以及c) 这些病理生理作用的分子基础。为了实现这些目标，我们开发了一个多学科的 细胞、器官和整个动物中P450亚型特异性表型的研究方法 水平，分析人类P450基因结构/表达变化与 以及对其代谢和功能后果的临床研究。Cyp2c和Cyp4a基因敲除 小鼠将被用来研究基因依赖性的变化：a)肾脏EET和/或20-HETE合成酶的表达， B)肾小管运输和/或血管反应性，以及c)全身血压和肾脏进展 疾病。CYP2C8/2C9或CYP4A11基因与血压、胰岛素敏感性、 尿液和血浆中的EET和20-HETE水平将被用来确定病理生理相关性。 变异等位基因、AA环氧化/羟化和个体对饮食盐变化的反应之间的关系 服用利尿剂或过氧化体增殖物激活受体(α)配体。我们的 长期目标是提供对P450二十烷类化合物在肾脏中作用的分子理解(S) 生理学，它们的机制和作用部位，以及与人类疾病的相关性。这些都是需要的 发展有意义的方法：a)明确定义人类病理生理学 意义，以及b)未来的药理靶向，以及临床诊断和干预。

The kidney plays a key role in the control of body fluid volume and composition, and tubular and/or hemodynamic dysfunction are common features of diseases such as hypertension and diabetes. The renal P450 arachidonic acid (AA) monooxygenase biosynthesizes hydroxy- and epoxy-AA derivatives that are known to modulate tubular transport and vascular reactivity. Animal models of P450 gene dysfunction confirmed the physiological importance of these enzymes, characterized their pathophysiological roles, and provided insights into the mechanism of action of their metabolites. Studies of the pathophysiological roles of human P450s identified associations between P450 gene variants with hypertension, the progression of renal disease, and with components of metabolic syndrome. This application proposes to build upon these studies and to address: a) mechanisms by which the P450-eicosanoids regulate renal tubular transport and vascular reactivity, b) the role of P450s in human hypertension and renal complications of diabetes, and c) the molecular basis of these pathophysiological roles. To achieve these goals, we developed a multidisciplinary approach for studies of P450-isoform specific phenotypes at the cellular, organ and whole animal levels, the analysis of associations between alterations in human P450 gene structure/expression and disease, and for clinical studies of their metabolic and functional consequences. Cyp2c and Cyp4a knockout mice will be used to study gene-dependent changes in: a) renal EET and/or 20-HETE synthase expression, b) tubular transport and/or vascular reactivity, and c) systemic blood pressure and the progression of renal disease. Associations between CYP2C8/2C9 or CYP4A11 genotypes with blood pressure, insulin sensitivity, and urine and plasma EET and 20-HETE levels will be explored to define pathophysiological correlations between variant alleles, AA epoxidation/hydroxylation, and individual responses to changes in dietary salt intake, the administration of diuretics, or peroxisomal proliferator activated receptor (alpha) ligands. Our long term goals are to provide a molecular understanding of role(s) of P450 eicosanoids in renal physiological, their mechanism and site of action, and relevance to human disease. These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention.