Renal cortical cyclooxygenase 2 expression is differentially regulated by angiotensin II AT ₁ and AT ₂ receptors

Abstract

Macula densa cyclooxygenase 2 (COX-2)-derived prostaglandins serve as important modulators of the renin-angiotensin system, and cross-talk exists between these two systems. Cortical COX-2 induction by angiotensin-converting enzyme (ACE) inhibitors or AT 1 receptor blockers (ARBs) suggests that angiotensin II may inhibit cortical COX-2 by stimulating the AT1 receptor pathway. In the present studies we determined that chronic infusion of either hypertensive or nonhypertensive concentrations of angiotensin II attenuated cortical COX-2. Angiotensin II infusion reversed cortical COX-2 elevation induced by ACE inhibitors. However, we found that angiotensin II infusion further stimulated cortical COX-2 elevation induced by ARBs, suggesting a potential role for an AT 2 receptor-mediated pathway when the AT1 receptor was inhibited. Both WT and AT2 receptor knockout mice were treated for 7 days with either ACE inhibitors or ARBs. Cortical COX-2 increased to similar levels in response to ACE inhibition in both knockout and WT mice. In WT mice ARBs increased cortical COX-2 more than ACE inhibitors, and this stimulation was attenuated by the AT2 receptor antagonist PD123319. In the knockout mice ARBs led to significantly less cortical COX-2 elevation, which was not attenuated by PD123319. PCR confirmed AT1a and AT2 receptor expression in the cultured macula densa cell line MMDD1. Angiotensin II inhibited MMDD1 COX-2, and CGP42112A, an AT2 receptor agonist, stimulated MMDD1 COX-2. In summary, these results demonstrate that macula densa COX-2 expression is oppositely regulated by AT1 and AT2 receptors and suggest that AT2 receptor-mediated cortical COX-2 elevation may mediate physiologic effects that modulate AT1-mediated responses. macula densa ͉ prostaglandin ͉ ACE inhibitor ͉ ARB T he conversion of arachidonic acid to prostaglandin H 2 by prostaglandin G 2 ͞H 2 synthase [cyclooxygenase (COX)] is a key enzymatic step that regulates the biosynthesis of prostaglandins and thromboxane. Prostaglandins regulate vascular tone and salt and water homeostasis in the mammalian kidney. Although inhibition of COX activity does not profoundly affect mammalian renal function under steady-state conditions, in conditions associated with increased angiotensin II production COX inhibition may lead to significant alterations in renal hemodynamics and function (1).In the kidney constitutive COX-1 is localized to mesangial cells, arteriolar endothelial cells, parietal epithelial cells of Bowman's capsule, and cortical and medullary collecting ducts. In contrast, in normal adult mammalian kidney COX-2 expression is localized to the macula densa and associated cortical thick ascending limb of Henle (cTAL) in the cortex and to a subset of medullary interstitial cells near the papillary tip (2). After chronic salt depletion, COX-2 expression in macula densa͞cTAL increases significantly, and macula densa-derived COX-2 metabolites have been implicated as modulators of the renin-angiotensin-aldosterone system by increasing renin expression and secretio...

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