Downregulation of renal CYP-derived eicosanoid synthesis in rats with diet-induced hypertension.
The incidence of essential hypertension increases with obesity; however, the mechanisms that link obesity with hypertension are unclear. Renal cytochrome P450 (CYP)-derived eicosanoids--hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DHETs)--have been shown to play an important role in the regulation of renal function, vascular tone, and blood pressure. The objective of this study was to examine CYP-derived eicosanoid synthesis in the different renal zones (cortex, medulla, and papilla) of rats fed a high fat diet (HF). Male Sprague-Dawley rats were fed a HF diet or regular rat chow for 10 weeks. After 10 weeks, HF rats showed significantly higher systolic blood pressure, body weight, and fat:body weight ratio. The renal omega-hydroxylase activity was decreased by 46% in cortex, 43% in medulla, and 46% in papilla of HF rats. The renal epoxygenase activity was decreased by 46% in cortex, 31% in medulla, and 56% in papilla of HF rats. Interestingly, the changes in the rate of 20-HETE and EET formation in different renal zones were consistent with the levels of expression of CYP4A and CYP2C23 proteins, respectively. Furthermore, there were no significant changes in the synthesis of these metabolites in the renal microvessels. These results demonstrate that HF diet causes the downregulation of CYP4A and CYP2C23 in renal tubules, and these proteins are responsible for renal 20-HETE and EET formation. The reduction in the synthesis of these eicosanoids may play an important role in the regulation of renal function and blood pressure in obesity-induced hypertension.
Wang
Mong-Heng
MH
Department of Physiology, Medical College of Georgia, Augusta, GA 30912, USA. mwang@mail.mcg.edu
Smith
Anita
A
Zhou
Yiqiang
Y
Chang
Hsin-Hsin
HH
Lin
Songbai
S
Zhao
Xueying
X
Imig
John D
JD
Dorrance
Anne M
AM
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001794:Blood Pressure; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet; D015536:Down-Regulation; D015777:Eicosanoids / Q000096:biosynthesis*; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000098:blood supply / Q000201:enzymology*; D008297:Male; D008833:Microcirculation / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain
C000717351:Cyp2c23 protein, rat; D015777:Eicosanoids; C400322:cytochrome P-450 CYP2C subfamily; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A