Renal tubular 20-HETE and EETs on sodium retention in

肾小管 20-HETE 和 EET 对钠潴留的影响

• 批准号: 7538418
• 负责人: Mong-Heng Wang
• 金额: $ 28.55万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538418
• 关键词: Abbreviations; Acids; Adenovirus Vector; Adenoviruses; Affect; Agonist; Alkane 1-monooxygenase; American; Anabolism; Arachidonic Acids; Attenuated; Blood Pressure; Blood Vessels; CYP4A1 gene; Carrier Proteins; Clofibrate; Control Locus; Cytochrome P450; Data; Diet; Down-Regulation; Eicosanoid Production; Eicosanoids; Enzymes; Epithelial; Fatty acid glycerol esters; Galactosidase; Gene Transfer; Glomerular Filtration Rate; Hexanoic Acids; Human; Hydroxyeicosatetraenoic Acids; Hypertension; In Vitro; Kidney; Mediator of activation protein; Microsomes; Modeling; Molecular; Na(+)-K(+)-Exchanging ATPase; Obesity; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Potassium Channel; Production; Proteins; Rattus; Regulation; Renal Blood Flow; Renal Plasma Flow; Renal function; Renal tubule structure; Research Personnel; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Sodium; Sodium Channel; Structure of ascending limb of Henle' s loop; Testing; Tubular formation; Up-Regulation; Vascular resistance; Vasodilation; adenoviral-mediated; base; design; epithelial Na+ channel; feeding; formamidine; hexanoic acid; high risk; in vivo; kidney vascular structure; male; new therapeutic target; obesity treatment; overexpression; pressure; programs; propenylphosphonic acid; research study; sodium-hydrogen exchanger 3; vasoconstriction

This is a proposal to investigate the contribution of renal tubular cytochrome P450-derived eicosanoids, 20-HETE and EETs, to sodium retention in male rats fed the high-fat (HF) diet, which is an accepted model for obesity-induced hypertension. 20-HETE and EETs have been shown to affect vascular tone and tubular sodium transport in vitro, as well as renal function and blood pressure in vivo. Preliminary studies demonstrate that renal 20-HETE and EET production and the enzymes CYP4A1, CYP4A8, and 2C23, which catalyze this production, are significantly decreased in renal microsomes after rats have been fed the HF diet for 10 weeks. The down-regulation of eicosanoid production occurs in the proximal tubules, but not in the renal microvessels. Moreover, the HF diet results in sodium retention and hypertension, and is associated with down-regulation of peroxisome proliferator-activated receptor a (PPARa). Furthermore, clofibrate, a selective CYP4A inducer, decreases sodium retention in male rats fed the HF diet. Based on these findings, the underlying hypothesis is that the HF diet decreases 20-HETE (through PPARa pathway) and EET production, which may increase the expression of sodium-transporter proteins or modulate their activity, and consequently causes sodium retention and hypertension. The Specific Aims in this proposal are to test the hypothesis that: (1) selective induction of tubular 20-HETE and EETproduction can attenuate obesity-induced hypertension by reducing sodium retention and altering renal function; (2) adenoviral-mediated tubular overexpression of CYP4A and CYP2C23 can attenuate obesity-induced hypertension by reducing sodium retention and altering renal function; (3) 20- HETE and EETs can modulate tubular Na+-K+-ATPase and regulate the expression of NHE-3, ROMK, and ENaC and contribute to sodium retention in HF rats; and (4) activation of PPARa contributes to up-regulation of tubular 20-HETE production in vitro and in HF rats. These proposed studies will elucidate the role of renal tubular 20-HETE and EETs in regulating sodium retention in obese HF rats and provide important new information regarding the role of these eicosanoids in obesity-induced hypertension.

这是一个研究肾小管细胞色素P450衍生的类花生酸，20-HETE的贡献的建议。 和雌二醇对高脂（HF）饮食雄性大鼠钠潴留的影响，HF饮食是肥胖诱导的公认模型， 高血压20-已显示HETE和EclO在体外影响血管张力和肾小管钠转运， 以及体内的肾功能和血压。初步研究表明，肾脏20-HETE和EET 生产和酶CYP 4A 1，CYP 4A 8，和2C 23，催化这种生产，显着降低 在大鼠喂食HF饲料10周后的肾微粒体中。类花生酸产生的下调 发生在近端小管中，但不在肾微血管中。此外，HF饮食导致钠潴留， 高血压，并且与过氧化物酶体增殖物激活受体α（PPARa）的下调有关。 此外，氯贝特，一种选择性CYP 4A诱导剂，降低HF饲料喂养的雄性大鼠的钠潴留。基于 根据这些发现，潜在的假设是HF饮食降低了20-HETE（通过PPARa途径）和EET。 产生，其可增加钠转运蛋白的表达或调节其活性，以及 从而引起钠潴留和高血压。本提案的具体目的是检验假设 结论：（1）选择性诱导肾小管20-HETE和EET的产生可通过以下途径减轻肥胖诱导的高血压： 减少钠潴留和改变肾功能;（2）腺病毒介导的肾小管CYP 4A过表达， CYP 2C 23可通过减少钠潴留和改变肾功能来减轻肥胖引起的高血压;（3）20- HETE和Eclase可调节肾小管Na+-K+-ATP酶，调节NHE-3、ROMK和ENaC的表达， PPARa的激活有助于肾小管20-HETE的上调 在体外和HF大鼠中产生。这些拟议的研究将阐明肾小管20-HETE和EAE的作用， 在调节肥胖HF大鼠的钠潴留，并提供重要的新信息，这些作用 类花生酸在肥胖性高血压中的作用

项目成果

Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension.

• DOI: 10.1038/ki.2008.300
• 发表时间: 2008-10
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Zhou, Yiqiang;Luo, Pengcheng;Chang, Hsin-Hsin;Huang, Hui;Yang, Tianxin;Dong, Zheng;Wang, Cong-Yi;Wang, Mong-Heng
• 通讯作者: Wang, Mong-Heng