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: 8111789
• 负责人: Youfei Guan
• 金额: $ 19.55万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8111789
• 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; 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.

糖尿病肾病是美国终末期肾病的主要原因。 各州。最近，抗糖尿病药物噻唑烷二酮类(TZDS)和降血脂的贝特类药物 结合和激活过氧化物酶体增殖物激活受体γ(PPARγ)和α (PPARpha)分别被发现不仅可以改善血糖和血脂水平，而且还可以 延缓2型糖尿病患者糖尿病肾病的进展。新出现的证据表明， 细胞色素P450花生四烯酸(AA)单加氧酶(Cyp4a omega-羟基酶和Cyp2c 环氧合酶)受PPARpha和PPARGamma控制，Cyp4a衍生的20-HETE Cyp2c缺失的EETs可能是两种核受体的内源性配体。这些 数据强烈表明，P450AA单加氧酶代谢产物20-HETE和EETS可能 调节PPAR功能，在糖尿病肾病发病机制中发挥重要作用。目前的建议 旨在研究P450 AA单加氧酶在肾保护作用中的作用。 PPARα和PPARγ激动剂，并确定这些酶和它们的 代谢产物参与糖尿病肾病的发生发展。为了实现这些目标，我们 建议：1)研究Cyp4a和PPAR受体相互作用在糖尿病肾病中的作用。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)缺乏 Cyp4a10和Cyp4a14(Cyp4a10-/-和Cyp4a14-/-)或过表达Cyp4a12(Cyp4a12 转基因)，以确定cyp4a酶在糖尿病肾病中的作用以及Gyp4a与 PPAR激动剂的肾脏保护作用；2)检测Cyp2c44和PPAR受体的作用 在目录号码中的交互作用。Cyp2c44全局缺失对糖尿病肾病进展的影响将在 1型和2型糖尿病小鼠。携带肾小球Cyp2c44基因的1型和2型糖尿病小鼠 将使用loxP/CRE系统来弥补不足，并将跟踪糖尿病肾病的进展。这个 Cyp2c44在PPAR激动剂的有益肾脏作用中的作用也将被确定。这些 研究不仅应该提供对Cyp4a和Cyp2c在糖尿病肾病发病机制中的作用的见解 但也阐明了EET和HETE影响糖尿病肾病的可能的潜在机制。