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

描述(由申请人提供)：这是一项研究肾小管细胞色素P450衍生的二十碳二烯类化合物，20-HETE和EETs对喂食高脂(HF)饮食的雄性大鼠钠滞留的贡献的提案，高脂(HF)饮食是肥胖性高血压的公认模型。20-HETE和EETs已被证明在体外影响血管张力和肾小管钠转运，以及在体内影响肾功能和血压。初步研究表明，大鼠喂饲HF饲料10周后，肾脏微粒体中20-HETE和EET的产生以及催化这一产生的酶CYP4A1、CYP4A8和2C23显著减少。二十烷基类化合物的产生下调发生在近端小管，而不是在肾微血管。此外，HF饮食导致钠滞留和高血压，并与过氧化物酶体增殖物激活受体a(PPARa)的下调有关。此外，氯贝特，一种选择性的细胞色素P4A诱导剂，减少了喂食HF饮食的雄性大鼠的钠滞留。基于这些发现，潜在的假设是HF饮食减少了20-HETE(通过PPARa途径)和EET的产生，这可能增加了钠转运蛋白的表达或调节了它们的活性，从而导致钠滞留和高血压。该建议的具体目的是验证如下假设：(1)选择性诱导肾小管上皮细胞20-HETE和EETs的产生可以通过减少钠滞留和改变肾功能来降低肥胖诱导的高血压；(2)腺病毒介导的肾小管上皮细胞色素P4A和细胞色素P42C23的过表达可以通过减少钠滞留和改变肾功能来降低肥胖诱导的高血压；(3)20-HETE和EETs可以调节肾小管Na-K ATPase，调节NHE-3、ROMK和ENaC的表达，从而促进钠离子滞留；(4)激活PPARa有助于在体外和心衰大鼠体内上调20-HETE的产生。这些拟议的研究将阐明肾小管20-HETE和EETs在调节肥胖HF大鼠钠滞留中的作用，并提供关于这些二十烷类化合物在肥胖性高血压中作用的重要新信息。

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.