Role of Eicosanoids in Renal Function

肾脏在控制体液容量和成分方面起着关键作用，而肾小管和/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，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，并对它们的代谢产物的作用机制提供了深入的了解。对人类P450的病理生理学作用的研究发现，P450基因变异与高血压、肾脏疾病的进展以及代谢综合征的组成部分之间存在关联。这项申请建议以这些研究为基础，解决：a)P450-二十烷类化合物调节肾小管运输和血管反应性的机制，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，我们开发了一种多学科的方法，用于在细胞、器官和整个动物水平上研究P450-亚型的特定表型，分析人类P450基因结构/表达变化与疾病之间的关系，以及临床研究其代谢和功能后果。Cyp2c和Cyp4a基因敲除小鼠将被用来研究以下方面的基因依赖性变化：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)全身血压和肾脏疾病的进展。我们将探索CYP2C8/2C9或CYP4A11基因与血压、胰岛素敏感性、尿液及血浆EET和20-HETE水平的关系，以确定不同等位基因、AA环氧化/羟化以及个体对饮食盐摄入量、利尿剂或过氧体增殖物激活受体(α)配体变化的反应之间的病理生理学相关性。我们的长期目标是提供对P450二十烷类化合物在肾脏生理中的作用(S)的分子理解，它们的机制和作用部位，以及与人类疾病的相关性。这些都是开发有意义的方法所必需的：a)明确定义人类的病理生理意义，以及b)未来的药理学靶向，以及临床诊断和干预。 相关性：高血压和糖尿病是心血管、脑部和肾脏疾病发病率和死亡率的主要原因，它们的流行以及多种医疗和社会经济后果使它们成为一个重大的健康挑战。预计肾脏P450在人类高血压和糖尿病中的作用的定义将导致对这些疾病的早期诊断和治疗的新方法，并有助于防止其破坏性后果。

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. Relevance: Hypertension and diabetes are leading causes of cardiovascular, cerebral, and renal disease morbidity and mortality, and their prevalence and multiple medical and socio-economic consequences make them a major health challenge. It is expected that the definition of a role for kidney P450s in human hypertension and diabetes will lead to new approaches for the early diagnosis and treatment of these diseases, and contribute to prevent their devastating consequences.