(Hypertension. 1999;34:503-507.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Inhibition of the Renin-Angiotensin System Upregulates Cyclooxygenase-2 Expression in the Macula Densa
From the Institut für Physiologie, Universität Regensburg (K.W., H.C., A.K.), and Abteilung Nephrologie, Medizinische Klinik IV, Universität Erlangen Nürnberg (A.H., M.G-S., K.F.H.), Germany.
Correspondence to Konrad Wolf, PhD, Institut für Physiologie I, Universitätsstr 31, Universität Regensburg, D-93040 Regensburg, Germany. E-mail konrad.wolf{at}vkl.uni-regensburg.de
Abstract—The expression of
cyclooxygenase 2 (COX-2) in the late thick
ascending limb, including the macula densa, is found to be upregulated
in an activated renin-angiotensin system.
How this upregulation is managed is not yet known. We therefore
considered the possibility that the stimulation of COX-2 expression is
triggered by the activation of the renin-angiotensin
system. For this purpose, we treated male Sprague-Dawley rats with the
angiotensin I–converting enzyme inhibitor
ramipril (10 mg/kg per day), the angiotensin II type 1
(AT1) receptor blocker losartan (30 mg/kg per day),
and the angiotensin II type 2 (AT2) receptor
blocker PD123319 (6 mg/kg per day) for 4 days. We determined the
expression of COX-2 mRNA and protein in the renal cortex. We found that
ramipril and the AT1 receptor blocker losartan
increased COX-2 mRNA and COX-2 immunoreactivity in the macula densa
4-fold, whereas the AT2 blocker PD123319 showed no
effect. A low-salt diet (0.02% wt/wt) stimulated COX-2 expression in
the kidney cortex <2-fold. The combination of a low-salt diet with
ramipril led to a further increase of COX-2 mRNA and COX-2
immunoreactivity compared with low salt or ramipril alone. These data
indicate that endogenous angiotensin II
apparently inhibits COX-2 expression in the macula densa via
AT1 receptors and can therefore not account for the
stimulation of COX-2 expression associated with an activated
renin-angiotensin system. Because macula densa–derived
prostaglandins are considered stimulators of renin
secretion and renin synthesis, inhibition of macula densa COX-2 by
angiotensin II could form a novel indirect negative
feedback control of the renin system.
Key Words: renin • prostaglandins • angiotensin II
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