Eicosanoids and Renal Microvascular Function

现在认识到肾脏CYP 450单加氧酶的花生四烯酸代谢物是肾血管和肾小管功能的重要调节剂。肾脏CYP 450代谢产物在盐和水平衡的控制以及器官疾病的病理生理学中发挥关键的生理作用。本研究项目的长期目标是检验CYP 450控制特定类花生酸生成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，CYP 450环氧酶和羟化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，由内皮细胞产生的CYP 450表氧化酶代谢产物具有抗高血压特性，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（EDHF）。另一方面，CYP 450羟化酶代谢产物20-HETE由肾血管平滑肌细胞产生，引起血管收缩，并被认为是一种促高血压因子。我们将通过研究来扩展这些初步发现，以提供CYP 450花生酸代谢物在肾微血管功能中作用的分子和机制描述。我们将确定参与肾脏的细胞信号传导途径和膜电流。 心肌细胞对11，12-EET和14，15-EET和20-HETE的反应。我们还将测定CYP 450 代谢物在肾小球前肾微血管的激素和旁分泌调节中的作用。最后，我们将确定由遗传控制的CYP 450活性变化诱导的传入小动脉表型改变。总之，该项目将整合目前对肾脏微血管CYP 450途径功能意义的认识，并结合生物分子方法的进展，以描述11，12-EET和14，15-EET和20-HETE的作用机制以及该途径的生理和/或病理生理学重要性。

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.