P450-dependent arachidonic acid metabolism and angiotensin II-induced renal damage
| Autor: | Horst Honeck, Wolf-Hagen Schunck, Eva Kaergel, Juergen Theuer, Alexander Mullally, Dominik N. Müller, Friedrich C. Luft, Erdenechimeg Shagdarsuren |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Epoxygenase
medicine.medical_specialty Hypertension Renal End organ damage Angiotensinogen Biology Kidney Cytochrome P-450 CYP2J2 Pathogenesis Animals Genetically Modified Rats Sprague-Dawley Renin-Angiotensin System chemistry.chemical_compound Cytochrome P-450 Enzyme System Internal medicine Renin Internal Medicine medicine Animals Renal Insufficiency Cytochrome P450 Family 2 Arachidonic Acid Angiotensin II Cytochrome P450 medicine.disease Rats Kinetics Endocrinology medicine.anatomical_structure chemistry Steroid 16-alpha-Hydroxylase Steroid Hydroxylases Albuminuria biology.protein Oxygenases Arachidonic acid Aryl Hydrocarbon Hydroxylases medicine.symptom |
| Zdroj: | Hypertension (Dallas, Tex. : 1979). 40(3) |
| ISSN: | 1524-4563 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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