Cytochrome P450 Arachidonic Acid Metabolism and Regulation of Renal Function

糖尿病肾病（DN）是美国终末期肾病（ESRD）的主要原因 国家。最近，抗糖尿病药物噻唑烷二酮类药物（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 (PPARγ) 和 α (PPARα) 分别被发现不仅可以改善血糖和血脂水平，还可以 减缓 2 型糖尿病 DN 的进展。新出现的证据表明，表达 细胞色素 P450 花生四烯酸 (AA) 单加氧酶（Cyp4a omega-羟化酶和 Cyp2c 环氧化酶）受 PPARα 和 PPARγ 控制，而 Cyp4a 衍生的 20-HETE Cyp2c 衍生的 EET 可以作为两种核受体的内源配体。这些 数据强烈表明 P450 AA 单加氧酶代谢物 20-HETE 和 EET 可能 调节 PPAR 功能并在 DN 发病机制中发挥重要作用。目前的建议 旨在研究 P450 AA 单加氧酶在肾脏保护作用中的作用 PPARα 和 PPARgamma 激动剂，并确定这些酶及其 代谢物参与糖尿病肾病的发展。为了实现这些目标我们 建议：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 诱导的或秋田犬）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）来定义 cyp4a 酶在 DN 中的作用以及 Gyp4a 与 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。全局 Cyp2c44 缺失对 DN 进展的影响将在 1型和2型糖尿病小鼠。肾小球 Cyp2c44 基因 1 型和 2 型糖尿病小鼠 将使用 LoxP/Cre 系统弥补缺陷，并跟踪 DN 的进展。的 Cyp2c44 在 PPAR 激动剂有益肾脏作用中的作用也将得到确定。这些 研究不仅应该深入了解 Cyp4a 和 Cyp2c 在 DN 发病机制中的作用 还阐明了 EET 和 HETE 影响 DN 的可能潜在机制。

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.