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

基本信息

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
项目类别：
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

项目摘要

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.

Diabefic肾病（DN）是联合终末期肾脏疾病（ESRD）的主要原因国家。最近，抗糖尿病噻唑烷二酮（TZD）和低脂肪纤维纤维纤维结合并激活过氧化物酶体增殖物激活的受体伽马（Ppargamma）和α （分别发现PPARALPHA）不仅可以改善血糖和脂质水平减慢2型糖尿病中DN的进展。新兴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 环氧酶）由pparalpha和ppargamma控制，以及CYP4A衍生的20-Hete CYP2C底膜可以用作两个核受体的动力配体。这些数据强烈表明P450 AA单加氧酶代谢产物20-Hete和Eets可能调节PPAR功能并在DN的发病机理中起重要作用。目前的提议旨在研究p450 AA单加氧酶在侵蚀性效应中的作用 pparalpha和ppargamma激动剂，并确定这些酶是否及其代谢物参与糖尿病肾脏疾病的发展。为了实现这些目标提出：1）表征CYP4A和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Akita）和2型糖尿病小鼠（DB/dB） CYP4A10和CYP4A14（CYP4A10 - / - 和CYP4A14 - / - ）或过表达CYP4A12（CYP4A12 转基因）定义CYP4A酶在DN和GYP4A与gyp4a之间的关联的作用 PPAR激动剂的肾脏保护作用； 2）检查CYP2C44和PPAR受体的作用 dn中的相互作用。全球CYP2C44删除对DN进展的影响将在 1型和2型糖尿病小鼠。 1型和2型糖尿病小鼠带有肾小球CYP2C44基因使用LOXP/CRE系统将使DN不足，并遵循DN的进展。这 CYP2C44在PPAR激动剂的有益肾作用中的作用也将得到确定。这些研究不仅应提供有关CYP4A和CYP2C在DN发病机理中的作用的见解但还阐明了Eets和Hetes影响DN的可能基本机制。