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: 8521250
• 负责人: RAYMOND C. HARRIS
• 金额: $ 18.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521250
• 关键词: Accounting; Acute; Acute Renal Failure with Renal Papillary Necrosis; Agonist; Alkane 1-monooxygenase; Apoptotic; Arachidonic Acids; 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; Growth Factor; Homeostasis; Human; Hydroxyeicosatetraenoic Acids; 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 Blood Flow; Renal function; Reperfusion Therapy; Role; Second Messenger Systems; Signal Transduction; Signal Transduction Pathway; Sodium; Sodium Channel; Sodium Chloride; Somatotropin; System; Transgenic Mice; Tubular formation; Water; base; epithelial Na+ channel; in vivo; insight; overexpression; preconditioning; relating to nervous system; response; salt intake; salt sensitive; second messenger

Project #4 will investigate 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 regulation of renal epithelial salt and water homeostasis. In addition 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 protection 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 III) 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

项目＃4将研究P450花生四烯酸（AA）代谢产物在调节肾上皮细胞功能和生长中的作用。该PPG和其他PPG进行的研究表明，P450 AA单氧酶途径在人类高血压的病理生理学，盐敏感性纳地钠和肾脏疾病的进展中的作用。越来越多的证据表明，EET和20-Hete都充当重要的亚钠因子，对肾上皮细胞中钠转运蛋白具有直接抑制作用。基于我们小组和其他人的先前研究，我们建议EET和20-HETE主要用作某些生长因子和激素的细胞内第二使者，从而调节肾上皮细胞中的其他信号转导途径以及离子通道以及转运蛋白。具体而言，我们将探索他们作为表皮生长因子（EGF）和多巴胺的第二使者的作用，这两种激动剂在调节肾上皮盐和水稳态方面具有重要作用。除了作为介导功能小管反应的第二个使者的作用外，我们和其他人还记录了P450 AA代谢物在体外的有丝分裂和抗凋亡作用，我们假设它们在Vivo哺乳动物肾脏的缺血性损伤中也很重要。为了调查这些问题，我们提出了以下特定目的： 具体目的i）研究EET的细胞内信号传导机制，作为肾脏EGF受体激活和功能反应的第二个使者。 具体目标ii）研究P450 AA代谢物作为多巴胺介导的纳特里雷SIS的第二使者的作用 特定目标iii）研究EET在急性小管损伤中的细胞保护和恢复中的作用，我们假设肾脏肾脏损伤可能导致哺乳动物的P450表达和功能增加