Eicosanoids and Renal Microvascular Function

类二十烷酸与肾微血管功能

• 批准号: 7459643
• 负责人: John D Imig
• 金额: $ 21.79万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459643
• 关键词: 11,12-epoxy-5,8,14-eicosatrienoic acid; Address; Animals; Antihypertensive Agents; Arachidonic Acids; Calcium Channel; Caliber; Cells; Cyclic AMP; Disease; Eicosanoids; Endothelium; Equilibrium; Functional disorder; Funding; Gene Targeting; Generations; Hand; Hormonal; Ion Channel; Kidney; Kidney Diseases; Knowledge; L-Type Calcium Channels; Link; Mediating; Mediator of activation protein; Membrane; Microcirculation; Mixed Function Oxygenases; Molecular; Muscle Cells; Numbers; Organ; P2X-receptor; Pathway interactions; Physiological; Play; Principal Investigator; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteinase-Activated Receptors; Regulation; Research Personnel; Research Project Grants; Rho-associated kinase; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Sodium Chloride; Testing; Tubular formation; Vascular resistance; Vasodilation; Water; Work; base; hypertensive factor; kidney vascular structure; paracrine; programs; response; rho; second messenger; vasoconstriction

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.

现在人们认识到，肾脏 CYP450 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 CYP450 代谢物在控制盐和水平衡以及器官疾病的病理生理学中发挥着关键的生理作用。该研究项目的长期目标是检验以下一般假设：CYP450 控制特定类二十烷酸的生成，为肾微血管功能提供重要介质。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发挥着非常重要的作用。先前的研究发现内皮细胞产生的CYP450环氧化酶代谢物具有抗高血压特性，并提出11,12-EET和14,15-EET是肾脏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 CYP450 花生四烯酸代谢物在肾微血管功能中的作用的分子和机制描述。我们将确定肾脏中涉及的细胞信号传导途径和膜电流 肌细胞对 11,12-EET、14,15-EET 和 20-HETE 的反应。我们还将确定 CYP450 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 CYP450 活性的基因控制变化引起的传入小动脉表型改变。总而言之，该项目将把肾微血管 CYP450 通路的功能意义的当前知识与生物分子方法的进展相结合，以描述 11,12-EET 和 14,15-EET 和 20-HETE 的作用机制以及生理和功能。 /或该途径的病理生理学重要性。