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

描述（由申请方提供）：这是一项研究肾小管细胞色素P450衍生的类花生酸、20-HETE和雌二醇对高脂（HF）饲料喂养的雄性大鼠钠潴留的贡献的提案，HF饲料是公认的肥胖诱导高血压模型。20-已证明HETE和Eclad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，大鼠喂食HF饲料10周后，肾脏20-HETE和EET的产生以及催化这种产生的酶CYP 4A 1、CYP 4A 8和2C 23在肾微粒体中显著降低。类二十烷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饮食导致钠潴留和高血压，并且与过氧化物酶体增殖物激活受体a（PPARa）的下调相关。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，这可能增加钠转运蛋白的表达或调节其活性，从而导致钠潴留和高血压。本提案的具体目的是检验以下假设：（1）选择性诱导肾小管20-HETE和EET产生可通过减少钠潴留和改变肾功能来减轻肥胖诱导的高血压;（2）腺病毒介导的肾小管CYP 4A和CYP 2C 23过表达可通过减少钠潴留和改变肾功能来减轻肥胖诱导的高血压;（3）20- HETE和Ehrs可调节肾小管Na+-K+ ATP酶，调节NHE-3、ROMK和ENaC的表达，并参与HF大鼠钠潴留;（4）PPARa的激活有助于体外和HF大鼠肾小管20-HETE产生的上调。这些拟议的研究将阐明肾小管20-HETE和雌二醇在调节肥胖HF大鼠钠潴留中的作用，并提供有关这些类花生酸在肥胖诱导的高血压中的作用的重要新信息。

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.