(Hypertension. 2000;36:610.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Cytochrome P450–Dependent Renal Arachidonic Acid Metabolism in Desoxycorticosterone Acetate–Salt Hypertensive Mice
From the Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.
Correspondence to Friedrich C. Luft, MD, Charité Campus-Buch, Franz Volhard Clinic, Wiltberg Str 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
Abstract—Cytochrome P450
(P450)-dependent arachidonic acid metabolites may act
as mediators in the regulation of vascular tone and renal function. We
studied arachidonic acid hydroxylase activities in
renal microsomes from normotensive NMRI mice, desoxycorticosterone
acetate (DOCA)-salt hypertensive mice, and DOCA-salt mice treated with
either lovastatin or bezafibrate, both of which improve
hemodynamics in this model. Control renal microsomes
had arachidonic acid hydroxylase activities of 175±12
pmol · min-1 · mg-1. The
metabolites formed were 20- and 19-hydroxyarachidonic
acid, representing 
80% and 20% of the total
hydroxylation. Treatment with DOCA-salt resulted in significantly
decreased hydroxylase activities (to 84±4 pmol ·
min-1 · mg-1) of the total microsomal
P450 content and a decrease in immunodetectable Cyp4a proteins.
Lovastatin had no effect on these variables, whereas
bezafibrate increased arachidonic acid hydroxylase
activities to 163±12 pmol · min-1 ·
mg-1. In situ hybridization with probes for Cyp4a-10, 12,
and 14 revealed that Cyp4a-14 was the P450 isoform most strongly
induced by bezafibrate. The expression was concentrated in the cortical
medullary junction and was localized predominantly in the proximal
tubules. In conclusion, these results suggest that the capacity to
produce 20-hydroxyarachidonic acid is impaired in the
kidneys of DOCA-salt hypertensive mice. Furthermore, bezafibrate may
ameliorate hemodynamics in this model by restoring
P450-dependent arachidonic acid hydroxylase activities.
Lovastatin, on the other hand, exerts its effects via
P450-independent mechanisms.
Key Words: mice • kidney • arachidonic acid • cytochrome P450 • hydroxyeicosatetraenoic acids
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