Eicosanoids and Renal Microvascular Function

现在认识到，花生四烯酸代谢产物的肾脏CYP450单加氧酶是肾血管和肾小管功能的重要调节剂。肾脏CYP450代谢物在控制盐和水的平衡以及器官疾病的病理生理中起着关键的生理作用。本研究项目的长期目标是验证CYP450控制特定类二十烷醇的产生提供肾微血管功能重要介质的一般假设。其他人和我们已经确定CYP450环氧化酶和羟化酶代谢物在影响传入小动脉功能中起着非常重要的作用。前期研究发现内皮产生的CYP450环氧合酶代谢物具有抗高血压的特性，并提出11,12- EET和14,15-EET是肾微循环中的内皮源性超极化因子（EDHFs）。另一方面，CYP450羟化酶代谢物，20-HETE，由肾血管平滑肌细胞产生，引起血管收缩，并被认为是一种高血压因子。我们将通过开展研究来扩展这些初步发现，以提供CYP450花生果酸代谢物在肾微血管功能中的作用的分子和机制描述。我们将确定参与肾脏的细胞信号通路和膜电流

It is now recognized that arachidonic acid metabolites of the kidney CYP450 monooxygenases are important regulators of renal vascular and tubular function. Kidney CYP450 metabolites play key physiological roles in the control of salt and water balance and the pathophysiology of organ disease. The long-term objective of this research project is to test the general hypothesis that CYP450 controlled generation of specific eicosanoids provides important mediators of renal microvascular function. Others and we have established that CYP450 epoxygenase and hydroxylase metabolites play a very important role in influencing afferent arteriolar function. Previous studies have found that CYP450 epoxygenase metabolites produced by the endothelium have anti-hypertensive properties and proposed that 11,12- EET and 14,15-EET are endothelium-derived hyperpolarizing factors (EDHFs) in the renal microcirculation. On the other hand, the CYP450 hydroxylase metabolite, 20-HETE, is produced by renal vascular smooth muscle cells, causes vasoconstriction and has been implicated as a pro-hypertensive factor. We will extend these initial findings by performing studies to provide a molecular and mechanistic description of the role of CYP450 arachionate metabolites in renal microvascular function. We will determine the cell singaling pathways and membrane currents involved in the renal myocyte responses to 11,12-EET and 14,15-EET and 20-HETE. We will also determine CYP450 metabolites role in hormonal and paracrine regulation of the preglomerular renal microvasculature. Lastly, we will determine the afferent arteriolar phenotypic alterations induced by genetically controlled changes in CYP450 activity. Taken together, this project will integrate current knowledge of the functional significance of the renal microvascular CYP450 pathway with advances in biomolecular approaches to describe the mechanism of action of 11,12-EET and 14,15-EET and 20-HETE and the physiological and/or pathophysiological importance of this pathway.