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(Hypertension. 2006;48:323.)
© 2006 American Heart Association, Inc.

Original Articles

Differentiation of Cyclooxygenase 1- and 2–Derived Prostanoids in Mouse Kidney and Aorta

Zhonghua Qi; Hui Cai; Jason D. Morrow; Matthew D. Breyer

From the Division of Nephrology (Z.Q., M.D.B.), Department of Medicine, and the Departments of Internal Medicine (H.C.), Pharmacology (J.D.M.), and Molecular Physiology and Biophysics (M.D.B.), Vanderbilt University, Nashville, Tenn; and the Veterans Administration Medical Center (M.D.B.), Nashville, Tenn.

Correspondence to Zhonghua Qi, S-3223 MCN, Vanderbilt University Medical Center, 1161 21st Ave South, Nashville, TN 37232. E-mail zhonghua.qi{at}vanderbilt.edu

	Abstract

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Accumulating evidence indicates cyclooxygenase (COX) 1 and COX2 differentially regulate cardiovascular and renal function. We have demonstrated previously in mice that COX2 inhibition enhances angiotensin II-induced hypertension, and COX1 inhibition attenuates the pressor effect of angiotensin II. To further elucidate the mechanism underlying the functional difference of COX1 versus COX2 inhibition, the present studies examined the prostaglandin (PG) profiles derived in COX1- or COX2-inhibited mouse kidney and aorta using gas chromatographic/mass spectrometric assays. PGE₂ is the most abundant prostanoid in both renal cortex and medulla in normal C57BL/6J mice, followed by PGI₂, PGF₂ and thromboxane A₂. In contrast PGI₂ was most abundant in aorta followed by thromboxane A₂, PGE₂, and PGF₂. PGD₂ was undetectable in control kidney or aorta. At baseline, inhibition of COX1 decreased total prostaglandins in renal cortex, medulla, and aorta, whereas COX2 inhibition decreased total prostaglandins only in renal medulla. Angiotensin II infusion significantly increased COX2-dependent/COX1-independent PGE₂ and PGI₂ in renal cortex and medulla. Angiotensin II also significantly increased renal PGF₂ in cortex, but not in medulla, through both COX1- and COX2-dependent mechanisms. These studies demonstrate that although COX1 primarily contributes to basal prostanoid production in the kidney and aorta, angiotensin II increases renal vasodilator prostanoids predominately via COX2 activity. These effects may contribute to the specific effect of COX2 inhibitors to increase blood pressure.

Key Words: prostaglandins • cyclooxygenase • angiotensin II • kidney • mice

	Introduction

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Cyclooxygenase (COX) catalyzes the synthesis of prostaglandins (PGs) from arachidonate.¹ Two isozymes encoded by different genes, COX1 and COX2, mediate this process.¹ Accumulating evidence indicates COX1 and COX2 activity differentially influence renal and cardiovascular function.^2–10 For example patients receiving a selective COX2 inhibitor exhibited an increased incidence of thrombotic cardiovascular events and hypertension.^2,3,8 In contrast, low-dose aspirin, which primarily inhibits COX1, has been widely used for preventing cardiovascular events.⁴ Deterioration of renal function may also be observed in patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) or COX2 selective inhibitors.¹¹ However, the mechanism by which COX1 versus COX2 activity differentially regulates renal and cardiovascular function remains to be elucidated.

COXs modulate biological and pathological processes primarily via their intermediate metabolite, PGH₂, and downstream products, including PGE₂, PGI₂, thromboxane (Tx) A₂, PGF₂, and PGD₂.^1,12 These prostanoids play diverse roles in regulating renal and cardiovascular function. Although PGE₂ and PGI₂ are potent vasodilators, TxA₂ and PGF₂ are potent vasoconstrictors.^12–17 Differential synthesis of these PGs by COX1 versus COX2 could account for the distinct cardiovascular effects of COX1 and COX2 inhibition.

We have demonstrated previously in mice that selective inhibition of COX2 activity enhanced the pressor effects of angiotensin (Ang) II on blood pressure and renal medullary blood flow while inhibiting COX1 attenuated Ang II-induced hypertension.⁷ The present studies examined the identity of the PGs produced in the kidney and aorta of control and Ang II-infused mice in the presence and absence of COX1 or COX2 selective inhibition.

	Methods

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Materials
The selective COX1 inhibitor SC58560 and COX2 inhibitor SC58236 were generously provided by Peter C. Isakson and Karen Seibert (Pharmacia). The COX1 and COX2 knockout mice were provided by Dr Langenbach at the National Institute of Environmental Health Sciences in North Carolina and maintained in Vanderbilt University. Ang II was the product of Sigma-Aldrich. The C57BL/6J mice were purchased from the Jackson Laboratories. All of the animal protocols were approved by the Institutional Animal Care and Use Committee of Vanderbilt University, and the animal studies were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Selective Inhibition of COX Activity
The protocols for selectively inhibiting COX1 or COX2 activity have been reported previously.⁷ Briefly, 5 groups of female mice were studied: Group 1, C57BL/6J mice (n=8) treated with a selective COX1 inhibitor, SC58560 (15 mg/mL in stock solution and 1:500 diluted in tap water), in drinking water for 7 days; Group 2, COX1 knockout mice (n=9); Group 3, C57BL/6J mice (n=6) received a selective COX2 inhibitor, SC58236 (3 mg/mL in stock solution and 1:500 diluted), in drinking water for 7 days; Group 4, COX2 knockout mice (n=6); and Group 5, control mice: mice received vehicle (95% polyethylene glycol 200 and 5% Tween-20) in drinking water for 7 days (n=8). Mice in each group were randomly divided into 2 subgroups receiving either Ang II or vehicle infusion.

Animal Surgery and Ang II Infusion
As described previously,⁷ the COX selective inhibitor or vehicle-pretreated mice, as well as COX1 or COX2 knockout mice, were anesthetized with ketamine (100 µg per gram of body weight, IM) plus inactin (100 µg per gram of body weight, IP). After tracheostomy, PE10 catheter was inserted into the left carotid artery to monitor blood pressure. Additional PE10 tubing was inserted into left jugular vein for drug infusion. Ang II (150 pmol/kg per minute) or 0.9% NaCl solution was infused continuously after 120 minutes of equilibration. Mean arterial pressure was monitored using a Blood Pressure Analyzer (BPA model 300, Micro-Med Inc).

Determination of Prostanoids in Renal Cortex, Medulla, and Aorta
After infusion of Ang II or 0.9% NaCl solution, kidneys were removed, and renal cortex and medulla were separated under microscopy. The abdominal aorta was isolated, and the blood inside the vessel was washed out in the ice-cold 0.9% NaCl solution. The concentration of 5 major prostanoids or their metabolites (PGE₂, 6-keto-PGF₁, TxB₂, PGF₂, and PGD₂) was determined using gas chromatographic/negative ion chemical ionization mass spectrometric assays.¹⁸ The lowest detectable concentration for prostanoids is &0.05 ng/g tissue. To examine whether the perfusion protocol affects basal prostanoid production, kidneys and aortas from an additional group of age-matched C57BL/6J female mice (n=4) were harvested immediately after anesthesia. There is no significant difference in renal and aortic PGE₂, 6-keto-PGF₁, TxB₂, and PGF₂ between these 2 groups of mice (data no shown). PGD₂ was below detectable levels (<0.05 ng/g tissue) in all 3 of the tissues studied. These results indicate that the infusion protocol used in the present studies per se did not significantly influence prostanoid production.

Statistics
All of the data were expressed as mean±SE. For statistic analysis, the prostanoid concentration was converted to logarithm value. For multiple group analysis, 1-way ANOVA and post hoc Fisher’s protected least significant difference test were used. For 2-group comparison, t test was performed. P<0.05 was considered significant.

	Results

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Contribution of COX1 Versus COX2 to Basal Renal and Aortic PG Production
In normal untreated C57BL/6J mice, PGE₂, 6-keto-PGF₁, PGF₂, and TxB₂ were detected in renal cortex, medulla, and aorta (Figure 1). PGE₂ was the major PG in both renal cortex and medulla, followed by PGI₂ and PGF₂, with little TxB₂. In contrast, PGI₂ predominated aorta followed by TxB₂, PGE₂, and PGF₂.

View larger version (17K): [in this window] [in a new window]   Figure 1. Basal prostanoid profiles in renal cortex, medulla, and aorta in normal mice. Bars in each group from left to right represent PGE2, 6-keto-PGF1 (6-Keto), PGF2, and TxB2, n=8 in each group.

Knocking out the COX1 gene (ptgs1) or treating mice with a COX1 inhibitor but not COX2 inhibitor decreased total basal prostanoid production (the sum of all measured PGs) in both renal cortex and aorta (Table 1). In contrast, renal medullary total prostanoids significantly decreased in mice pretreated with either COX2 or COX1 inhibitor, supporting a major role for COX2 in renal medullary but not cortical PG synthesis.

View this table: [in this window] [in a new window]   TABLE 1. Basal Levels of Total Prostanoids in Renal Cortex, Medulla, and Aorta, and the Effects of COX1 or COX2 Selective Inhibition

In aorta COX1 inhibition but not COX2 inhibition decreased basal TxB₂ and 6-keto-PGF₁. Renal cortical 6-keto-PGF₁ was also COX1 dependent (Table 2). In contrast, basal renal medullary PGI₂ and PGE₂, as well as renal cortical PGE₂, seems to be derived from both COX1 and COX2 activity. Thus, COX1 plays a primary role in basal cortical and aortic prostanoid synthesis, whereas COX2 activity contributes more significantly to renal medullary prostanoid production.

View this table: [in this window] [in a new window]   TABLE 2. Effects of Selective COX1 or COX2 Inhibition on Basal Prostanoid Production (ng/g Tissue) in Mouse Kidney and Aorta

Effects of Ang II on Prostanoid Production in Renal Cortex, Medulla, and Aorta
Ang II infusion significantly increased synthesis of the vasodilators PGE₂ and PGI₂ (6-keto-PGF₁) in both renal cortex and medulla (Figure 2). Ang II also increased PGF₂ in renal cortex but not in medulla. In contrast, Ang II did not significantly change aortic PGE₂, 6-keto-PGF₁, PGF₂, or TxB₂, but Ang II dramatically increased aortic PGD₂.

View larger version (11K): [in this window] [in a new window]   Figure 2. Effects of Ang II on prostanoid production in renal cortex, medulla, and aorta. *P<0.05 vs control mice (CN) in each group.

Contribution of COX1 Versus COX2 to Ang II-Stimulated Prostanoids
Selective inhibition of COX2 but not COX1 attenuated Ang II-stimulated PGE₂ and 6-keto-PGF₁ in both renal cortex and medulla (Figure 3), indicating that Ang II stimulates renal PGE₂ and PGI₂ via COX2. In contrast, either COX1 or COX2 inhibition blocked the increase in cortical PGF₂ or aortic PGD₂ induced by Ang II.

View larger version (23K): [in this window] [in a new window]   Figure 3. Effects of COX1 vs COX2 selective inhibition on Ang II-stimulated prostanoid production. Bars in each group from left to right represent control, COX1 inhibitor pretreated (COX1i), COX1 null (COX1–/–), COX2 inhibitor pretreated (COX2i), and COX2 null (COX2–/–) mice. Data are expressed as changes in mean value of PGs between Ang II-infused mice and their respective controls (eg, COX1–/– vs COX1–/– +Ang II). *Changes achieving statistical significance vs non-Ang II-infused respective controls (P<0.05).

Prostanoids in COX2-Deficient Mice
COX2 null mice exhibit renal dysgenesis predominately affecting the renal cortex.⁵ Consistent with this, COX2 null mice exhibited significantly increased renal cortical TxB₂ (presumably COX1 derived) as compared with normal controls (Table 2). The basal levels of renal cortical PGE₂, TxB₂, and PGF₂ in COX2 null mice were also higher than that in COX2 inhibitor-treated mice. Prostanoid levels in renal medulla and aorta are similar in COX2 null mice and mice pretreated with COX2 inhibitor. After Ang II infusion, COX2 null mice exhibited decreased cortical PGE₂, TxB₂, and PGF₂ levels (presumably COX1 derived; Figure 3), a response quite different from mice pretreated with COX2 inhibitor, where Ang II increased PG synthesis (see above).

	Discussion

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Both clinical and animal studies show that COX1 and COX2 differentially regulate the renal and cardiovascular systems.^2–7,9,10 Defining the mechanisms by which COX2 inhibitors increase cardiovascular risk as opposed to the decreased cardiovascular risk associated with aspirin represents a major challenge. The present studies examined whether differential COX1 and COX2 inhibition could contribute to altered renal and vascular prostanoid production. These studies used tissues from mice shown previously to exhibit distinct blood pressure and renal hemodynamics effects of COX1 versus COX2 inhibition.⁷ The specificity of these COX1 and COX2 inhibitors has been demonstrated in these mice and other studies.^7,19–21

The renal cortex and medulla exhibited a similar basal prostanoid profile, with PGE₂ being the most abundant prostanoid followed by the prostacyclin metabolite 6-keto-PGF₁, then PGF₂ and TxB₂. The predominance of PGE₂ is consistent with previous studies showing that PGE₂ receptors are abundant and widely expressed in renal cortex and medulla.¹² In the unstimulated aorta, 4 major prostanoids, PGE₂, PGI₂, TxA₂, and PGF₂, were also detected. In contrast to the kidney, PGI₂ was the most abundant prostanoid in aorta. Furthermore, the amount of PGs per gram of tissue was dramatically higher than that in the kidney.

The present studies indicate that COX1 predominately contributes to basal PG production, because COX1 inhibition significantly decreased total PG product in both kidney and aorta. Interestingly, COX2 significantly contributes to basal renal medullary PG production. It is also notable that basal aortic TxA₂ and PGI₂ primarily derived from COX1. This latter finding is consistent with previous studies indicating that COX1 is the major isozyme in vasculature.^22,23 COX2 only contributed significantly to basal PGI₂ production in the renal medulla, providing a possible site at which COX2 inhibitors target systemic PGI₂ production and thereby reduce urinary PGI₂ excretion.²⁴

Clinical studies suggested that the cardiovascular or renal adverse effects of NSAIDs and COX2 inhibitors are more likely to occur in a clinical setting accompanied by increased endogenous Ang II levels.^8,11 The present studies show that Ang II significantly increased the vasodilators PGE₂ and PGI₂ in both renal cortex and medulla. In contrast to basal PG production, Ang II-stimulated PG seems to be mediated predominately via COX2 activity, because it was attenuated by COX2 but not COX1 inhibition. COX2-derived PGE₂ and PGI₂ may serve as important vasodilators offsetting the vasoconstrictor effect of Ang II. Previous studies showed that COX2 inhibition decreases renal medullary blood flow after Ang II infusion,⁷ and, notably, immunochemistry studies indicated that renal medullary COX2 is expressed predominately in interstitial cells.^7,21 These findings suggest that PGE₂ and PGI₂ produced in the adjacent interstitial cells could play an important role in regulating vasa recta tone.

Chronic administration of COX2 inhibitors increasing blood pressure has been reported in humans and rodents.^3,9,25 In the previous studies, we found that chronic COX2 inhibition enhanced Ang II-induced hypertension but had no effect on baseline blood pressure, indicating an important role for COX2 activity in regulating the pressor effect of Ang II.⁷ Although the renal PG profiles are consistent with the notion that COX2 activity mediates Ang II-stimulated vasodilators PGE₂ and PGI₂, we could not distinguish the contribution of renal vascular COX2 from that expressed in tubules and other renal cells. Interestingly, aortic vasodilator PG was not significantly increased after acute Ang II infusion, suggesting that the aorta may not be the major site where COX2 plays an important role in regulating blood pressure in this setting.

Previous studies also demonstrated that COX1 inhibition attenuated blood pressure increase in both acute and chronic Ang II-treated animals.^7,26 A critical role of thromboxane A₂ receptor in mediating chronic Ang II-induced hypertension has also been reported.^26,27 Although the present studies indicated that basal aortic TxA₂, a potent vasoconstrictor, is predominately contributed by COX1 activity, TxA₂ production was not increased by Ang II. Alternatively, PGH₂ has been demonstrated as a potent vasoconstrictor and may play an important role in Ang II-induced hypertension via thromboxane A₂ receptor.^{14,17,28–30} In settings where COX1 predominates the vessel^22,23 and Ang II increases the availability of arachidonate,³¹ inhibition of COX1 activity may decrease PGH₂ and attenuate the pressor effort of Ang II. As discussed above, whether the aortic PG profile reflects that in the small resistance vessels needs to be studied.

Ang II also stimulates renal PGF₂, which is consistent with previous studies.³² The present studies further demonstrated that Ang II stimulated PGF₂ is primarily in renal cortex, and COX1 inhibition attenuates this increase. Although studies suggested that PGF₂ plays an important role in regulating renal electrolyte excretion,^33,34 PGF₂ may also serve as a potent vasoconstrictor, because the receptor affinity studies indicated that PGF₂ can bind to EP1 and EP3 receptors with relatively high affinity.^12,13 Whether reduced PGF₂ contributes to the effect of COX1 on blood pressure requires further study.

PGD₂ has been demonstrated to mediate allergy and regulate sleep.³⁵ Accumulating evidence indicates that PGD₂ also plays important roles in regulating renal and cardiovascular function.^36,37 For example, increased expression of renal PGD synthase in hypertensive patients has been reported.³⁷ In the present studies, we found that basal PGD₂ was below the detectable level in the kidney and aorta, consistent with previous studies.^13,38 Interestingly, Ang II significantly increased PGD₂ in aorta but not in the kidney. Whether PGD₂ synthesis mediates the pressor effect of Ang II remains to be determined.

A significant difference in renal PG profiles between COX2 null and COX2 inhibitor-treated mice was observed. Renal cortex from COX2 null mice exhibited higher basal levels of TxB₂ than wild-type controls, supporting a major contribution of COX1 to TxA₂ production. Renal cortical PGF₂ and PGE₂ in COX2 null mice also exhibited a tendency to increase, although they did not achieve statistical significance as compared with wild-type controls. Interestingly, Ang II administration significantly decreased cortical TxB₂, PGF₂, and PGE₂ in COX2 knockout mice. COX2 null mice developing renal dysgenesis have been demonstrated previously.⁵ The renal structural and developmental defects may be the main reason behind the discrepancy in renal PG profiles between COX2 null and COX2 inhibitor-treated mice. The renal COX1 expression in COX2 null mice has been examined previously, and no significant change in renal COX1 mRNA was observed.³⁹ Based on both our and previously published findings, we speculate that the significant increase in renal prostanoids seen in COX2 null mice is because of altered substrate availability or product degradation activity rather than COX1 protein levels. The physiological significance of the altered cortical prostanoids in COX2 null mice needs to be further defined, but from a clinical standpoint, the data from COX2 inhibitor-treated mice may more closely reflect the renal PG changes in an adult taking COX2 inhibitor. It is also notable that PG levels in COX1 null mice were also different from that in mice pretreated with COX1 inhibitor, especially at baseline. Because there is no obvious renal development defect reported in COX1 null mice, we speculate that a difference in inhibitor efficiency at COX1 may underlie this discrepancy.

Ang II stimulating PG production may be mediated via increased phospholipase A₂ activity leading to increased availability of arachidonic acid,³¹ upregulation of COX2 expression,^1,40 or both. Increased COX2 protein levels in response to a variety of stimuli, including Ang II, is usually not observed until 2 hours after stimulation in many cell types.^40–42 So, changes in COX2 expression during short-term Ang II treatment may be absent, and the alternated PGs seen in the present studies may be mediated via constitutively expressed COX isozymes in the tissues. This is supported by a preliminary immunoblotting study showing no detectable change in renal COX2 protein levels in Ang II-infused mice as compared with controls (data not shown).

It is also important to note that the blood pressure and PG profiles seen in the present studies reflect the effect of acute increased Ang II. Interestingly, the renal PG profiles seem to be consistent with previous chronic studies.^32,43 For example, Siragy et al³² have demonstrated that chronic Ang II infusion significantly increases renal interstitial PGE₂, 6-keto-PGF₁, and PGF₂ in mice, which is consistent with the PG profile in renal cortex after acute Ang II infusion. However, the effect of chronic increased Ang II on PG profiles in vasculature, especially in small resistant arteries, should be further defined.

Perspectives
PGs are involved in many physiological and pathological processes, thus, intervention of PG metabolism may be a potential therapeutic approach for many diseases.^2,7,8,44,45 However, the renal and cardiovascular adverse effects of NSAIDs, including COX2-selective inhibitors, have become a major concern of using these drugs.^2,3,8,11,44 The present study is an effort to elucidate the mechanism behind the beneficial and undesired adverse effects of NSAIDs by defining the renal and aortic PG profiles of COX1 and COX2 in mice at baseline and with increased Ang II. Our results indicate that COX1 and COX2 differentially mediate PG production in the kidney and aorta. COX1 activity plays an important role in basal aortic TxA₂, PGI₂, and renal cortical PGI₂ production. In contrast, COX2 activity contributes more significantly to basal renal medullary PGE₂ and PGI₂ production. In the setting of increased Ang II, COX2 activity seems to be more important in mediating vasodilator PGs in the kidney. Inhibition of different PGs by COX2 versus COX1 inhibition may contribute to the increased cardiovascular risk seen with COX2 inhibitor versus aspirin.^2–4,8

	Acknowledgments

 
Sources of Funding

This study was supported by National Institutes of Health grants DK 37097 (to M.D.B.); DK48831, CA77839, GM 15431, and ES 13125 (to J.D.M.); and the O’Brien Center Grant 2P50-DK39261 (to M.D.B.).

Disclosures

None.

Received March 16, 2006; first decision April 5, 2006; accepted June 2, 2006.

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