Eicosanoids and Renal Microvascular Function

目前认为，肾脏细胞色素P450单加氧酶的花生四烯酸代谢产物是肾血管和肾小管功能的重要调节因子。肾脏细胞色素P450代谢产物在调节水盐平衡和器官疾病的病理生理过程中起着重要的生理作用。这项研究项目的长期目标是检验一个普遍的假设，即CYP450控制特定二十烷类化合物的产生提供了肾脏微血管功能的重要介质。我们发现，细胞色素P450环氧合酶和羟基酶代谢产物在影响传入小动脉功能中起着非常重要的作用。以往的研究发现，内皮细胞产生的CYP450环氧合酶代谢产物具有降压作用，并提出11，12-EET和14，15-EET是肾微循环中的内皮衍生超极化因子。另一方面，细胞色素P450羟基酶代谢产物20-HETE由肾血管平滑肌细胞产生，引起血管收缩，已被认为是一种促高血压因子。我们将通过开展研究来扩展这些初步发现，以提供CYP450花生四烯酸代谢产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。 心肌细胞对11，12-EET和14，15-EET和20-HETE的反应。我们还将测定细胞色素P450 代谢产物在肾小球前微血管激素和旁分泌调节中的作用。最后，我们将确定由基因控制的细胞色素P450活性变化引起的传入小动脉的表型改变。综上所述，该项目将结合目前对肾脏微血管细胞色素P450途径的功能意义的认识和生物分子方法的进展来描述11，12-EET和14，15-EET和20-HETE的作用机制以及这一途径的生理和/或病理生理学意义。

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.