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

Item Type:Article
Title:A peroxisome proliferator-activated receptor-alpha activator induces renal CYP2C23 activity and protects from angiotensin II-induced renal injury
Creators Name:Muller, D.N. and Theuer, J. and Shagdarsuren, E. and Kaergel, E. and Honeck, H. and Park, J.K. and Markovic, M. and Barbosa-Sicard, E. and Dechend, R. and Wellner, M. and Kirsch, T. and Fiebeler, A. and Rothe, M. and Haller, H. and Luft, F.C. and Schunck, W.H.
Abstract: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-κB activation. We tested the hypothesis that the peroxisome proliferator-activated receptor-α-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-κB 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-α 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.
Keywords:8,11,14-Eicosatrienoic Acid, Angiotensin II, Angiotensinogen, Antilipemic Agents, Arachidonic Acid, Cytochrome P-450 Enzyme System, Cytoplasmic and Nuclear Receptors, Genetically Modified Animals, Hypertension, Immunohistochemistry, Kidney, Kidney Diseases, Liquid Chromatography, Mass Spectrometry, NF-kappa B, Polymerase Chain Reaction, Procetofen, Renin, Transcription Factors, Vasoconstrictor Agents, Western Blotting, Animals, Rats
Source:American Journal of Pathology
Publisher:American Society for Investigative Pathology
Page Range:521-532
Date:1 January 2004
Official Publication:https://doi.org/10.1016/S0002-9440(10)63142-2
PubMed:View item in PubMed

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