This Article Full Text Full Text (PDF) All Versions of this Article: 40/3/273    most recent 01.HYP.0000029240.44253.5Ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaergel, E. Articles by Schunck, W.-H. Search for Related Content PubMed PubMed Citation Articles by Kaergel, E. Articles by Schunck, W.-H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Kidney Failure Related Collections Animal models of human disease Hypertension - basic studies

(Hypertension. 2002;40:273.)
© 2002 American Heart Association, Inc.

Scientific Contributions

P450-Dependent Arachidonic Acid Metabolism and Angiotensin II–Induced Renal Damage

Eva Kaergel; Dominik N. Muller; Horst Honeck; Juergen Theuer; Erdenechimeg Shagdarsuren; Alexander Mullally; Friedrich C. Luft; Wolf-Hagen Schunck

From the Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic, HELIOS Kliniken-Berlin, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.

Correspondence to Wolf-Hagen Schunck, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany. E-mail schunck{at}mdc-berlin.de

Transgenic rats overexpressing both human renin and angiotensinogen genes (dTGR) develop hypertension, inflammation, and renal failure. We tested the hypothesis that these pathological features are associated with changes in renal P450-dependent arachidonic acid (AA) metabolism. Samples were prepared from 5- and 7-week-old dTGR and from normotensive Sprague-Dawley (SD) rats, ie, before and after the dTGR developed severe hypertension and albuminuria. At both stages, dTGR showed significantly lower renal microsomal AA epoxygenase and hydroxylase activities that reached 63% and 76% of the control values at week 7. Furthermore, the protein levels of several potential AA epoxygenases (CYP2C11, CYP2C23, and CYP2J) were significantly reduced. Immunoinhibition studies identified CYP2C23 as the major AA epoxygenase, both in dTGR and SD rats. Immunohistochemistry showed that CYP2C23 was localized in cortical and outer medullary tubules that progressively lost this enzyme from week 5 to week 7 in dTGR. CYP2C11 expression occurred only in the outer medullary tubules and was markedly reduced in dTGR compared with age-matched SD rats. These findings indicate site-specific decreases in the availability of AA epoxygenase products in the kidney of dTGR. In contrast to renal microsomes, liver microsomes of dTGR and SD rats showed no change in the expression and activity of AA epoxygenases and hydroxylases. We conclude that hypertension and end-organ damage in dTGR is associated with kidney-specific downregulation of P450-dependent AA metabolism. Because the products of AA epoxygenation have anti-inflammatory properties, this alteration may contribute to uncontrolled renal inflammation, which is a major cause of renal damage in dTGR.

Key Words: rats • kidney • cytochrome P450 • arachidonic acid • angiotensin II • inflammation • end-organ damage

This article has been cited by other articles:

				I. Fleming and R. Busse Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function Hypertension, April 1, 2006; 47(4): 629 - 633. [Abstract] [Full Text] [PDF]

				J. D. Imig Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases Am J Physiol Renal Physiol, September 1, 2005; 289(3): F496 - F503. [Abstract] [Full Text] [PDF]

				J. M. Seubert, F. Xu, J. P. Graves, J. B. Collins, S. O. Sieber, R. S. Paules, D. L. Kroetz, and D. C. Zeldin Differential renal gene expression in prehypertensive and hypertensive spontaneously hypertensive rats Am J Physiol Renal Physiol, September 1, 2005; 289(3): F552 - F561. [Abstract] [Full Text] [PDF]

				X. Zhao, T. Yamamoto, J. W. Newman, I.-H. Kim, T. Watanabe, B. D. Hammock, J. Stewart, J. S. Pollock, D. M. Pollock, and J. D. Imig Soluble Epoxide Hydrolase Inhibition Protects the Kidney from Hypertension-Induced Damage J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1244 - 1253. [Abstract] [Full Text] [PDF]

				Z. Yu, B. B. Davis, C. Morisseau, B. D. Hammock, J. L. Olson, D. L. Kroetz, and R. H. Weiss Vascular localization of soluble epoxide hydrolase in the human kidney Am J Physiol Renal Physiol, April 1, 2004; 286(4): F720 - F726. [Abstract] [Full Text] [PDF]

				D. N. Muller, J. Theuer, E. Shagdarsuren, E. Kaergel, H. Honeck, J.-K. Park, M. Markovic, E. Barbosa-Sicard, R. Dechend, M. Wellner, et al. A Peroxisome Proliferator-Activated Receptor-{alpha} Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury Am. J. Pathol., February 1, 2004; 164(2): 521 - 532. [Abstract] [Full Text] [PDF]

				X. Zhao, D. M. Pollock, D. C. Zeldin, and J. D. Imig Salt-Sensitive Hypertension After Exposure to Angiotensin Is Associated With Inability to Upregulate Renal Epoxygenases Hypertension, October 1, 2003; 42(4): 775 - 780. [Abstract] [Full Text] [PDF]