Renal tubular 20-HETE and EETs on sodium retention in obese rats

肾小管 20-HETE 和 EET 对肥胖大鼠钠潴留的影响

基本信息

批准号：
7178524
负责人：
Mong-Heng Wang
金额：
$ 28.49万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/7178524
关键词：
Abbreviations Acids Adenovirus Vector Adenoviruses Affect Agonist Alkane 1-monooxygenase American Anabolism Arachidonic Acids Attenuated Blood Pressure Blood Vessels Blood flow CYP4A1 gene Carrier Proteins Clofibrate Control Locus Cytochrome P450 DDMS Data Diet Down-Regulation Eicosanoid Production Eicosanoids Elevation 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 Protein Overexpression 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&apos s loop Testing Transcriptional Activation Tubular formation Up-Regulation Vascular resistance Vasodilation Week adenoviral-mediated base design epithelial Na+ channel feeding formamidine hexanoic acid in vivo kidney vascular structure male novel therapeutics obesity treatment pressure programs propenylphosphonic acid research study sodium-hydrogen exchanger 3 therapeutic target vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：这是研究肾小管细胞色素P450衍生的eicosanoids，20-Hete和eets的贡献，是喂养高脂饮食（HF）饮食的雄性大鼠钠的保留，这是肥胖诱导的高血压的公认模型。已证明20-HETE和EET会在体外影响血管张力和管状钠转运，以及体内的肾功能和血压。初步研究表明，在大鼠饮食中喂食HF饮食10周后，肾脏微粒体的肾小素显着降低了肾小球的肾脏20-HETE和EET产生以及CYP4A1，CYP4A8和2C23酶的促成这种产生的酶。类类产生的下调发生在近端小管中，但不在肾小管中。此外，HF饮食会导致钠保留和高血压，并与过氧化物酶体增殖物激活受体A（PPARA）的下调有关。此外，选择性CYP4A诱导剂的Clofibrate降低了喂养HF饮食的雄性大鼠的钠保留率。基于这些发现，基本的假设是HF饮食降低了20-HETE（通过PPARA途径）和EET产生，这可能会增加钠转运蛋白的表达或调节其活性，因此导致钠保留和高血压。该提案中的具体目的是检验以下假设：（1）选择性诱导20-HETE和ETETRACTUCTION可以通过减少钠保留和改变肾功能来减轻肥胖引起的高血压；（2）CYP4A和CYP2C23的腺病毒介导的管状过表达可以通过减少钠保留和改变肾功能来减轻肥胖诱导的高血压；（3）20- HETE和EET可以调节管状Na+K+ATPase，并调节NHE-3，ROMK和ENAC的表达，并有助于HF大鼠的钠保留。（4）PPARA的激活有助于在体外和HF大鼠体外和HF大鼠中上调。这些提出的研究将阐明肾小管20-HETE和EET在调节肥胖HF大鼠中钠保留率中的作用，并提供有关这些类花生素在肥胖引起的高血压中的作用的重要新信息。