Cytochrome P450 Arachidonic Acid Metabolism and Regulation of Renal Function

细胞色素 P450 花生四烯酸代谢与肾功能调节

• 批准号: 7758888
• 负责人: Youfei Guan
• 金额: $ 22.48万
• 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/7758888
• 关键词: 2,4-thiazolidinedione; Accounting; Affect; Agonist; Albuminuria; Alkane 1-monooxygenase; Antidiabetic Drugs; Antihypertensive Agents; Arachidonic Acids; Attenuated; Binding; Blood Glucose; Cell Proliferation; Chronic Kidney Failure; Clinical; Cytochrome P450; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; Eicosanoids; End stage renal failure; Enzymes; Epidemic; Epoxide hydrolase; Family; Fibrates; Fibrosis; Funding; Genes; Genetic Risk; Growth Factor; Hydrolase Gene; Hydroxyeicosatetraenoic Acids; Hyperglycemia; Individual; Inflammation; Injury; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Lead; Ligands; Lipids; Metabolic; Metabolic Control; Metabolism; Mixed Function Oxygenases; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; PPAR alpha; PPAR gamma; Pathogenesis; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Play; Population; Process; Protein Isoforms; Public Health; Regulation; Renal dialysis; Renal function; Reporting; Research; Role; Sodium; Syndrome; System; Thiazolidinediones; Transgenic Mice; Transgenic Organisms; United States; angiogenesis; attenuation; cardiovascular disorder risk; cost; cytochrome P-450 CYP2B19 (murine); cytochrome P-450 CYP2C subfamily; cytokine; design; diabetes management; diabetic; effective therapy; glomerular basement membrane; improved; inhibitor/antagonist; insight; insulin sensitivity; kidney vascular structure; lipid metabolism; novel strategies; overexpression; prevent; receptor; receptor function; therapeutic target; transcription factor; type I and type II diabetes; type I diabetic

Diabefic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States. Recently, antidiabetic thiazolidinediones (TZDs) and hypolipidemic fibrates which specifically bind and activate peroxisome proliferator-activated receptor gamma (PPARgamma) and alpha (PPARalpha), respectively, have been found not only improve blood glucose and lipid levels but also slow the progression of DN in type 2 diabetes. Emerging evidence suggests that expression of the cytochrome P450 arachidonic acid (AA) monooxygenases (Cyp4a omega-hydroxylases and Cyp2c epoxygenases) is under control of PPARalpha and PPARgamma, and the Cyp4a-derived 20-HETE and the Cyp2c-derlved EETs may serve as engogenous ligands for both nuclear receptors. These data strongly suggests that the P450 AA monooxygenase metabolites 20-HETE and EETs may modulate PPAR function and play an important role in the pathogenesis of DN. The present proposal is designed to study the role of the P450 AA monooxygenases in the renoprotective effects of PPARalpha and PPARgamma agonists and to determine whether these enzymes and their metabolites are involved in the development of diabetic kidney disease. To achieve these aims we propose to: 1) characterize the role of Cyp4a and PPAR receptor interaction in DN. We will create a type 1 diabetic mouse (STZ-induced or Akita) and a type 2 diabetic mouse (db/db) deficient for Cyp4a10 and Cyp4a14 (Cyp4a10-/- and Cyp4a14-/-) or overexpressing Cyp4a12 (Cyp4a12 transgenic) to define the role of cyp4a enzymes in DN and the association between Gyp4a and the renoprotective effects of PPAR agonists; 2) examine the role of Cyp2c44 and PPAR receptor interaction in DN. The effect of global Cyp2c44 delefion on the progression of DN will be examined in type 1 and type 2 diabetic mice. Type 1 and type 2 diabetic mice with glomerular Cyp2c44 gene deficiency will be made using the LoxP/Cre system and the progression of DN will be followed. The role of Cyp2c44 in the beneficial renal actions of PPAR agonists will also be determined. These studies should not only provide insights into the role of Cyp4a and Cyp2c in the pathogenesis of DN but also elucidate the possible underlying mechanisms by which EETs and HETEs affect DN.

糖尿病肾病（DN）是美国终末期肾病（ESRD）的主要原因。 States.最近，抗糖尿病的噻唑烷二酮（TZD）和降血脂贝特类药物，特别是 结合并激活过氧化物酶体增殖物激活受体γ（PPARgamma）和α 已经发现，分别与抗血小板生成因子α（PPARalpha）结合，不仅改善血糖和血脂水平， 延缓2型糖尿病DN的进展。新出现的证据表明， 细胞色素P450花生四烯酸（AA）单加氧酶（Cyp 4a ω-羟化酶和Cyp 2c 环氧酶）受PPARalpha和PPARgamma控制，Cyp 4a衍生的20-HETE Cyp 2c衍生的EkB可作为两种核受体的内源性配体。这些 数据有力地表明，P450 AA单加氧酶代谢物20-HETE和Ehrinate可能 调节PPAR的功能，在DN的发病机制中起重要作用。现时的建议 旨在研究P450 AA单加氧酶在肾保护作用中的作用， PPARalpha和PPARgamma激动剂，并确定这些酶和它们的 代谢物参与糖尿病肾病的发展。为了实现这些目标，我们 本研究拟：1）探讨CYP 4a与PPAR受体相互作用在DN中的作用。我们将创建一个 1型糖尿病小鼠（STZ诱导的或秋田）和2型糖尿病小鼠（db/db）， Cyp 4a 10和Cyp 4a 14（Cyp 4a 10-/-和Cyp 4a 14-/-）或过表达Cyp 4a 12（Cyp 4a 12 转基因），以确定cyp 4a酶在DN中的作用以及Gyp 4a与DN之间的关联。 PPAR激动剂的肾保护作用; 2）检查Cyp 2c 44和PPAR受体的作用 DN中的相互作用全面Cyp 2c 44缺失对DN进展的影响将在 1型和2型糖尿病小鼠。1型和2型糖尿病小鼠肾小球Cyp 2c 44基因的表达 将使用LoXP/Cre系统弥补缺陷，并跟踪DN的进展。的 还将确定Cyp 2c 44在PPAR激动剂的有益肾作用中的作用。这些 研究不仅要深入了解Cyp 4a和Cyp 2c在DN发病机制中的作用， 还阐明了EAE和HETE影响DN的可能机制。