A peroxisome proliferator-activated receptor-alpha activator induces renal CYP2C23 activity and protects from angiotensin II-induced renal injury

Autor: Hermann Haller, Anette Fiebeler, Dominik N. Müller, Marija Markovic, Joon-Keun Park, Michael Rothe, Horst Honeck, Maren Wellner, Eva Kaergel, Torsten Kirsch, Juergen Theuer, Erdenechimeg Shagdarsuren, Wolf-Hagen Schunck, Friedrich C. Luft, Ralf Dechend, Eduardo Barbosa-Sicard
Rok vydání: 2004
Předmět:
Epoxygenase
medicine.medical_specialty
Blotting
Western
Angiotensinogen
Peroxisome proliferator-activated receptor
Receptors
Cytoplasmic and Nuclear
Kidney
Cytochrome P-450 CYP2J2
Polymerase Chain Reaction
Mass Spectrometry
Pathology and Forensic Medicine
Animals
Genetically Modified
chemistry.chemical_compound
8
11
14-Eicosatrienoic Acid
Cytochrome P-450 Enzyme System
Fenofibrate
Internal medicine
Renin–angiotensin system
Renin
medicine
Animals
Humans
Vasoconstrictor Agents
Hypolipidemic Agents
chemistry.chemical_classification
Arachidonic Acid
biology
Angiotensin II
NF-kappa B
Kidney metabolism
Cytochrome P450
respiratory system
Immunohistochemistry
Rats
Endocrinology
medicine.anatomical_structure
chemistry
Hypertension
biology.protein
Arachidonic acid
Kidney Diseases
Chromatography
Liquid
Transcription Factors
Regular Articles
Zdroj: The American journal of pathology. 164(2)
ISSN: 0002-9440
Popis: 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.
Databáze: OpenAIRE
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