A peroxisome proliferator-activated receptor-alpha activator induces renal CYP2C23 activity and protects from angiotensin II-induced renal injury.
Cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolites are involved in the regulation of renal vascular tone and salt excretion. The epoxygenation product 11,12-epoxyeicosatrienoic acid (EET) is anti-inflammatory and inhibits nuclear factor-kappa B activation. We tested the hypothesis that the peroxisome proliferator-activated receptor-alpha-activator fenofibrate (Feno) induces CYP isoforms, AA hydroxylation, and epoxygenation activity, and protects against inflammatory organ damage. Double-transgenic rats (dTGRs) overexpressing human renin and angiotensinogen genes were treated with Feno. Feno normalized blood pressure, albuminuria, reduced nuclear factor-kappa B activity, and renal leukocyte infiltration. Renal epoxygenase activity was lower in dTGRs compared to nontransgenic rats. Feno strongly induced renal CYP2C23 protein and AA-epoxygenase activity under pathological and nonpathological conditions. In both cases, CYP2C23 was the major isoform responsible for 11,12-EET formation. Moreover, we describe a novel CYP2C23-dependent pathway leading to hydroxy-EETs (HEETs), which may serve as endogenous peroxisome proliferator-activated receptor-alpha activators. The capacity to produce HEETs via CYP2C23-dependent epoxygenation of 20-HETE and CYP4A-dependent hydroxylation of EETs was reduced in dTGR kidneys and induced by Feno. These results demonstrate that Feno protects against angiotensin II-induced renal damage and acts as inducer of CYP2C23-mediated epoxygenase activities. We propose that CYP-dependent EET/HEET production may serve as an anti-inflammatory control mechanism.
Muller
Dominik N
DN
HELIOS Klinikum-Berlin, Franz Volhard Clinic, and Medical Faculty of the Charité, Humboldt University of Berlin, Berlin. mueller@fvk-berlin.de
Theuer
Juergen
J
Shagdarsuren
Erdenechimeg
E
Kaergel
Eva
E
Honeck
Horst
H
Park
Joon-Keun
JK
Markovic
Marija
M
Barbosa-Sicard
Eduardo
E
Dechend
Ralf
R
Wellner
Maren
M
Kirsch
Torsten
T
Fiebeler
Anette
A
Rothe
Michael
M
Haller
Hermann
H
Luft
Friedrich C
FC
Schunck
Wolf-Hagen
WH
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D016718:Arachidonic Acid / Q000378:metabolism*; D015153:Blotting, Western; D002853:Chromatography, Liquid; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D013058:Mass Spectrometry; D016328:NF-kappa B / Q000187:drug effects; D016133:Polymerase Chain Reaction; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D012083:Renin / Q000235:genetics; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C000717351:Cyp2c23 protein, rat; D000960:Hypolipidemic Agents; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D012083:Renin; D015126:8,11,14-Eicosatrienoic Acid; D011345:Fenofibrate