Role of P450 Metabolites in Renal Tubular Epithelial Growth and Function

P450 代谢物在肾小管上皮生长和功能中的作用

• 批准号: 7758890
• 负责人: RAYMOND C. HARRIS
• 金额: $ 23.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758890
• 关键词: Accounting; Acute; Agonist; Alkane 1-monooxygenase; Apoptotic; Arachidonic Acids; Blood; Cells; Cytochrome P450; Cytoprotection; Development; Dopamine; Duct (organ) structure; Eicosanoids; Employee Strikes; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Excretory function; Functional disorder; Goals; Growth; Homeostasis; Human; Hypertension; In Vitro; Injury; Intracellular Second Messenger; Ion Channel; Ischemia; Kidney; Kidney Diseases; Lead; Maintenance; Mediating; Mediation; Mediator of activation protein; Mixed Function Oxygenases; Mus; Natriuresis; Natriuretic Factors; Pathway interactions; Production; Receptor Activation; Recovery; Regulation; Renal function; Reperfusion Therapy; Role; Second Messenger Systems; Signal Transduction; Signal Transduction Pathway; Sodium; Sodium Channel; Sodium Chloride; System; Transgenic Mice; Tubular formation; Water; base; epithelial Na+ channel; growth hormone regulating factor; in vivo; insight; overexpression; preconditioning; relating to nervous system; response; salt intake; salt sensitive; second messenger

Project #4 will invesfigate the role of P450 Arachidonic Acid (AA) metabolites in regulation of both function and growth of renal epithelial cells. Studies performed by this PPG and by others indicate a role for the P450 AA monooxygenase pathway in the pathophysiology of human hypertension, in salt sensitive natriuresis and in the progression of renal disease. There is increasing evidence that both EETs and 20-HETE serve as important natriuretic factors, with direct inhibitory effects on sodium transporters in renal epithelial cells. Based on previous studies by our group and by others, we propose that EETs and 20-HETE serve primarily as intracellular second messengers for certain growth factors and hormones, regulating other signal transduction pathways and ion channels and transporters in renal epithelial cells. Specifically, we will explore their role as second messengers for Epidermal Growth Factor (EGF) and dopamine, two agonists postulated to have important roles in regulafion of renal epithelial salt and water homeostasis. In addifion to their role as second messengers to mediate functional tubule responses, we and others have documented mitogenic and anti-apoptotic effects of P450 AA metabolites in vitro, and we hypothesize that they are also important in protecfion and recovery from ischemic injury of the mammalian kidney in vivo. In order to investigate these issues, we propose the follow specific aims: Specific Aim I) Investigate intracellular signaling mechanisms of EETs as second messengers for renal EGF receptor activation and functional responses. Specific Aim II) Investigate the role of P450 AA metabolites as second messengers for dopamine-mediated natriuresis Specific Aim 111) Investigate the role of EETs in cytoprotection and recovery from acute tubule injury We hypothesize that sublethal renal injury may lead to increased P450 expression and function in mammalian kidney to "precondition" against further ischemia/reperfusion induced injury.

项目#4将研究P450花生四烯酸（AA）代谢产物在调节这两种功能中的作用 和肾上皮细胞的生长。由PPG和其他人进行的研究表明P450的作用 AA单加氧酶途径在人类高血压的病理生理学、盐敏感性钠尿排泄和 肾脏疾病的进展。越来越多的证据表明，Ehrs和20-HETE都是 重要的利钠因子，对肾上皮细胞中的钠转运蛋白具有直接抑制作用。 基于我们小组和其他人以前的研究，我们提出Ehrs和20-HETE主要用于 作为某些生长因子和激素的细胞内第二信使，调节其他信号 在肾上皮细胞中的转导途径和离子通道和转运蛋白。具体来说，我们将探讨 它们作为表皮生长因子（EGF）和多巴胺的第二信使的作用，这两种激动剂被假定为 在调节肾上皮细胞水盐平衡中起重要作用。除了作为 第二信使介导功能性小管反应，我们和其他人已经记录了促有丝分裂和 P450 AA代谢物在体外的抗凋亡作用，我们假设它们在 保护和恢复体内哺乳动物肾脏的缺血性损伤。为了调查这些 我们提出以下具体目标： 具体目的I）研究EGF作为肾脏EGF第二信使的细胞内信号传导机制 受体激活和功能反应。 具体目的II）研究P450 AA代谢物作为多巴胺介导的第二信使的作用。 钠排泄 具体目的111）研究Escherichia coli在急性肾小管损伤的细胞保护和恢复中的作用。 假设亚致死性肾损伤可能导致哺乳动物P450表达和功能增加 肾脏“预处理”以防止进一步的缺血/再灌注诱导的损伤。