PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

Xueying Zhao, Jeffrey E. Quigley, Jianghe Yuan, Mong Heng Wang, Yiqing Zhou, John D. Imig

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg -1·day-1 for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 μM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% ± 11%) compared with lean controls (67% ± 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 μM of acetylcholine in obese Zucker rats (69% ± 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-α agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

Original languageEnglish (US)
Pages (from-to)H2187-H2195
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume290
Issue number6
DOIs
StatePublished - Jun 1 2006

Fingerprint

Fenofibrate
Zucker Rats
Peroxisome Proliferator-Activated Receptors
Eicosanoids
Cytochrome P-450 Enzyme System
Kidney
Acetylcholine
Blood Vessels
Down-Regulation
Proteins
High Fat Diet
Vasodilation
Triglycerides
Cholesterol
Insulin

Keywords

  • Cytochrome P-450
  • Kidney
  • Metabolic syndrome
  • Peroxisome proliferator-activated receptor-α
  • Renal vessels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats. / Zhao, Xueying; Quigley, Jeffrey E.; Yuan, Jianghe; Wang, Mong Heng; Zhou, Yiqing; Imig, John D.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 290, No. 6, 01.06.2006, p. H2187-H2195.

Research output: Contribution to journalArticle

@article{0499f2c2850a4956a2f953042e8d8b9e,
title = "PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats",
abstract = "Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg -1·day-1 for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15{\%} in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54{\%} and 18{\%}, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 μM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37{\%} ± 11{\%}) compared with lean controls (67{\%} ± 9{\%}). Chronic fenofibrate administration increased afferent arteriolar responses to 1 μM of acetylcholine in obese Zucker rats (69{\%} ± 4{\%}). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-α agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.",
keywords = "Cytochrome P-450, Kidney, Metabolic syndrome, Peroxisome proliferator-activated receptor-α, Renal vessels",
author = "Xueying Zhao and Quigley, {Jeffrey E.} and Jianghe Yuan and Wang, {Mong Heng} and Yiqing Zhou and Imig, {John D.}",
year = "2006",
month = "6",
day = "1",
doi = "10.1152/ajpheart.00937.2005",
language = "English (US)",
volume = "290",
pages = "H2187--H2195",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

AU - Zhao, Xueying

AU - Quigley, Jeffrey E.

AU - Yuan, Jianghe

AU - Wang, Mong Heng

AU - Zhou, Yiqing

AU - Imig, John D.

PY - 2006/6/1

Y1 - 2006/6/1

N2 - Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg -1·day-1 for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 μM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% ± 11%) compared with lean controls (67% ± 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 μM of acetylcholine in obese Zucker rats (69% ± 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-α agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

AB - Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg -1·day-1 for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 μM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% ± 11%) compared with lean controls (67% ± 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 μM of acetylcholine in obese Zucker rats (69% ± 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-α agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

KW - Cytochrome P-450

KW - Kidney

KW - Metabolic syndrome

KW - Peroxisome proliferator-activated receptor-α

KW - Renal vessels

UR - http://www.scopus.com/inward/record.url?scp=33744940507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33744940507&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00937.2005

DO - 10.1152/ajpheart.00937.2005

M3 - Article

C2 - 16501022

AN - SCOPUS:33744940507

VL - 290

SP - H2187-H2195

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6

ER -