Human Hypertension and P450 Co-Hydroxylases and Epoxygenases

肾脏在控制体液容量和成分以及管状和/或 血流动力学功能障碍是高血压、糖尿病等疾病的共同特征。肾 P450 花生四烯酸 (AA) 单加氧酶生物合成羟基和环氧-AA 衍生物， 已知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 证实了这些酶的生理重要性，表征了它们的病理生理作用，以及 提供了对其代谢物作用机制的见解。病理生理作用的研究 人类 P450 确定了 P450 基因变异与高血压、高血压的进展之间的关联 肾脏疾病，并伴有代谢综合征的成分。该应用程序建议以这些为基础 研究并解决：a) P450-类二十烷酸调节肾小管转运的机制和 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 研究细胞、器官和整个动物 P450 亚型特异性表型的方法 水平，分析人类 P450 基因结构/表达和变化之间的关联 疾病，以及对其代谢和功能后果的临床研究。 Cyp2c 和 Cyp4a 敲除 小鼠将用于研究以下方面的基因依赖性变化：a) 肾 EET 和/或 20-HETE 合酶表达， b) 肾小管运输和/或血管反应性，以及 c) 全身血压和肾病进展 疾病。 CYP2C8/2C9 或 CYP4A11 基因型与血压、胰岛素敏感性、 将探讨尿液和血浆 EET 和 20-HETE 水平以确定病理生理学相关性 变异等位基因之间、AA 环氧化/羟基化以及个体对饮食盐变化的反应 摄入、服用利尿剂或过氧化物酶体增殖物激活受体（α）配体。我们的 长期目标是提供对 P450 类二十烷酸在肾病中的作用的分子理解。 生理学、其机制和作用部位以及与人类疾病的相关性。这些是需要的 制定有意义的方法：a）人类病理生理学的明确定义 意义，b) 未来的药理学靶向、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.