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(American Journal of Pathology. 2004;164:521-532.)
© 2004 American Society for Investigative Pathology

A Peroxisome Proliferator-Activated Receptor- Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury

Dominik N. Muller^*, Juergen Theuer^*, Erdenechimeg Shagdarsuren^*, Eva Kaergel, Horst Honeck, Joon-Keun Park, Marija Markovic^*, Eduardo Barbosa-Sicard, Ralf Dechend^*, Maren Wellner^*, Torsten Kirsch, Anette Fiebeler^*, Michael Rothe, Hermann Haller, Friedrich C. Luft^* and Wolf-Hagen Schunck

From HELIOS Klinikum-Berlin,^* Franz Volhard Clinic, and Medical Faculty of the Charité, Humboldt University of Berlin, Berlin; the Max Delbrück Center for Molecular Medicine, Berlin-Buch; the Department of Medicine-Nephrology, Hannover Medical School, Hannover; and FILT GmbH, Berlin-Buch, Germany

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-B activation. We tested the hypothesis that the peroxisome proliferator-activated receptor--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-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 themajor 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- 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.

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