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 i n 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL082733-01
Application #
7013302
Study Section
Special Emphasis Panel (ZRG1-RUS-E (04))
Program Officer
Barouch, Winifred
Project Start
2006-02-15
Project End
2009-11-30
Budget Start
2006-02-15
Budget End
2006-11-30
Support Year
1
Fiscal Year
2006
Total Cost
$317,000
Indirect Cost
Name
Georgia Health Sciences University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Luo, Pengcheng; Wang, Mong-Heng (2011) Eicosanoids, ?-cell function, and diabetes. Prostaglandins Other Lipid Mediat 95:1-10
Luo, Pengcheng; Chang, Hsin-Hsin; Zhou, Yiqiang et al. (2010) Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis. J Pharmacol Exp Ther 334:430-8
Luo, Pengcheng; Zhou, Yiqiang; Chang, Hsin-Hsin et al. (2009) Glomerular 20-HETE, EETs, and TGF-beta1 in diabetic nephropathy. Am J Physiol Renal Physiol 296:F556-63
Zhou, Yiqiang; Luo, Pengcheng; Chang, Hsin-Hsin et al. (2008) Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension. Kidney Int 74:1040-8
Ping, Ansong; Xi, Jinlei; Prasad, Balakrishna M et al. (2008) Contributions of nucleus accumbens core and shell GluR1 containing AMPA receptors in AMPA- and cocaine-primed reinstatement of cocaine-seeking behavior. Brain Res 1215:173-82
Rivera, Ian; Zhang, Shali; Fuller, B Scott et al. (2007) P2 receptor regulation of [Ca2+]i in cultured mouse mesangial cells. Am J Physiol Renal Physiol 292:F1380-9
Huang, Hui; Morisseau, Christophe; Wang, JingFeng et al. (2007) Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. Am J Physiol Renal Physiol 293:F342-9
Huang, Hui; Chang, Hsin-Hsin; Xu, Yue et al. (2006) Epoxyeicosatrienoic Acid inhibition alters renal hemodynamics during pregnancy. Exp Biol Med (Maywood) 231:1744-52