(Hypertension. 1999;34:96-101.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Cyclooxygenase-2 Inhibition Decreases Renin Content and Lowers Blood Pressure in a Model of Renovascular Hypertension
From the George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to R.C. Harris, MD, Division of Nephrology, S 3322, MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail Ray.Harris{at}mcmail.vanderbilt.edu
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Abstract—It has been proposed that the macula densa participates in the regulation of increased renin expression in renovascular hypertension (RVH) and that prostaglandins may be among the mediators of macula densa function. We have previously shown that in renal cortex, cyclooxygenase-2 (COX-2) expression is localized to the macula densa and surrounding cortical thick ascending limb and increases in high-renin states, such as salt restriction and angiotensin-converting enzyme inhibition. In the present studies, we examined the effect of the selective COX-2 inhibitor SC58236 on plasma renin activity (PRA) and renal renin expression in RVH in rats. The aorta was coarcted between right and left renal arteries, and animals received either SC58236 or vehicle for 1 week. At day 8, vehicle-treated coarcted rats were hypertensive (mean carotid arterial blood pressure: 138±3 versus 87±2 mm Hg in sham-operated controls; n=9 to 11; P<0.001) and exhibited a disparity of kidney size (ratio left/right kidney: 0.78±0.04 versus 1.02±0.02; n=9 to 10; P<0.001). PRA increased significantly (84.6±6.5 versus 9.0±1.4 ng angiotensin I [Ang I] per milliliter per hour; n=8 to 9; P<0.01). In the coarcted rats, neither renin mRNA expression nor renin activity of the right kidney was altered (renin/GAPDH mRNA: 1.12±0.05-fold levels in control rats; n=6; P=NS; renin activity: 23.4±1.8 versus 27.1±3.4 ng Ang I per hour per milligram protein; n=8 to 9; P=NS). However, the renin mRNA of the left kidney increased to 3.0±0.6-fold of control (n=6), and the renin activity increased to 189.0±28.6 ng Ang I per hour per milligram protein (n=8; P<0.01). Expression of COX-2 mRNA and immunoreactive protein increased in the affected left kidney but was not different from control in the unaffected right kidney. SC58236 treatment to coarcted rats did not affect kidney size (ratio left/right kidney: 0.79±0.06; n=9). However, PRA was significantly decreased compared with the vehicle-treated coarcted rats (19.8±2.8 ng Ang I per milliliter per hour; n=9; P<0.01). The left kidney renin mRNA and renin content were also decreased (1.7±0.3-fold control; n=6; P<0.05; and 45.7±7.6 ng Ang I per hour per milligram protein; n=9; P<0.01, respectively), while renin mRNA and renin content of the right kidney were not altered. SC58236 lowered mean arterial blood pressure (122±5 mm Hg; n=14; P<0.05 compared with vehicle). A significant correlation was observed between PRA and mean blood pressure (r=0.75; P<0.01). In summary, these studies indicate that the selective COX-2 inhibitor SC58236 decreases renin production and release in RVH and suggest an important role for COX-2 regulation of the renin-angiotensin system.
Key Words: renin • cyclooxygenase • hypertension, renal • macula densa • kidney
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Introduction |
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Both experimental models and clinical experience have indicated that prostaglandins are involved in the regulation of renal renin expression and release.1 2 3 4 In addition to physiological regulation of renin in response to alterations in intravascular volume status, prostaglandins have also been implicated in the mediation of increased renin production by the affected kidney(s) in renovascular hypertension (RVH).5 6 The source of these modulating prostaglandins has been in dispute, in part because of uncertainty about the mechanisms that regulate the abnormal renin production in RVH. Previous studies suggested that baroreceptors or abnormal sympathetic tone or both were the primary mediators of renin production and release in RVH,1 thereby implicating the local release of prostacyclin from afferent arterioles. However, more recent studies have suggested that macula densa signaling may also contribute to increased renin production in RVH.7 8
The conversion of arachidonic acid to prostaglandin H2 by prostaglandin G2/H2 synthase (cyclooxygenase) is a key enzymatic step in the regulation of prostaglandin synthesis.9 Two isoforms of cyclooxygenase (COX) exist: constitutive (COX-1) and inducible (COX-2).10 11 COX-1 is the most prevalent isoform in the mammalian kidney, and immunoreactive COX-1 has been localized to arteries and arterioles, glomeruli, and collecting ducts. However, no immunoreactive COX-1 is expressed in the cortical thick ascending limb of Henle (cTALH) or macula densa.12
In previous studies, we determined that COX-2 expression in the renal cortex was localized to occasional cells of the cTALH in the region of the macula densa.13 With salt depletion, COX-2 expression increased significantly in cTALH and in the macula densa.13 14 15 More recently, we have determined that administration of angiotensin-converting enzyme (ACE) inhibitors to animals on a normal diet also increased cTALH/macula densa COX-2 expression, and we have determined that a selective inhibitor of COX-2 decreased the increases in plasma and kidney renin activity and renal renin mRNA expression that result from ACE inhibition.16 Similarly, Harding et al17 have determined that COX-2 inhibitors inhibited renin increases in response to salt depletion. Recent studies by Hartner et al18 have indicated that COX-2 expression increased in the affected kidney in a model of 2-kidney, 1 clip hypertension and was associated with coordinate increases in renin expression. Therefore, the present studies were designed to determine whether, in an experimental model of RVH, inhibition of COX-2 activity altered renin expression and affected the associated hypertension.
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Sprague-Dawley rats were from Harlan (Indianapolis, Ind). Anti–COX-2 antibodies were from Cayman. The selective COX-2 inhibitor SC58236, which exhibits a COX-2/COX-1 selectivity of 1780-fold,19 was a gift from Searle Monsanto Co. 32P-CTP (3000 Ci/mmol) was from Amersham, angiotensin I (Ang I) (125I) radioimmunoassay was from NEN, and rat renin cDNA was a gift of Kevin Lynch, University of Virginia. Other reagents were purchased from Sigma Chemical Co.
Animal Model and Experimental Procedures
Male Sprague Dawley rats, weighing 150 to 200 g, were
divided into 3 groups: sham-operated rats were used as control;
coarctated rats were gavaged with SC58236 (10 mg/kg body wt per day in
1% methylcellulose) or vehicle only for 7 days, beginning on the day
after surgery. All experiments were performed within the guidelines of
the Institutional Animal Care and Use Committee of Vanderbilt
University School of Medicine.
Surgical procedures were performed with the use of ketamine hydrochloride xylazine (Rampum) (9:1) anesthesia. RVH was produced by partial subdiaphragmatic aortic constriction modified from previously described techniques.5 20 21 Briefly, after median laparotomy, the abdominal aorta was isolated between the right and left exits of the renal artery. Cotton thread was used to constrict the aorta, with the extent of narrowing limited by a blunted 19-gauge needle (1 mm OD). At day 7, the left carotid artery was cannulated under ketamine hydrochloride/xylazine anesthesia, and blood pressure was determined with a blood pressure analyzer (Digi-Med) 1 hour after recovery from anesthesia. Mean blood pressure (MAP) was calculated as the average of 10 measurements. After measurement of MAP, blood was collected from the catheter for plasma renin activity (PRA) measurements, rats were killed, both kidneys were weighed separately, and tissue was processed as indicated below.
Renin Activity
At the time of death, blood was collected on ice in EDTA (1
mg/mL blood). The plasma was separated and frozen at -20°C until
assayed. For renal tissue renin measurement, the kidneys were
homogenized in 0.1 mol/L Tris-HCl, pH 7.4, containing
3.4 mmol/L 8-hydroxyquinolone sulfate, 0.25 mmol/L EDTA,
0.1 mmol/L phenylmethylsulfonyl fluoride, 1.6 mmol/L
dimercaprol, 5 mmol/L sodium tetrathionate, and 0.1% Triton
X-100.22 The concentration of protein was determined with
a BCA protein assay kit (Pierce). After centrifugation
of the homogenate, the supernatant was incubated for 1 hour
with excess exogenous renin substrate (rat plasma obtained from rats
nephrectomized 48 hours before collection). Renin was analyzed
by radioimmunoassay with a (125I)Ang I kit
(NEN).
RNA Extraction and Northern Blotting
Renal cortex RNA was extracted by the acid guanidinium
thiocyanate–phenol chloroform method, as described
previously.23 RNA samples were electrophoresed in a
denatured agarose gel and transferred to nitrocellulose membranes and
hybridized with a 1.4-kb 32P-labeled
BamHI/HindIII cDNA fragment of rat
renin.24 The membranes were then stripped and
rehybridized with GAPDH.
Immunoblotting
Renal cortex was homogenized in 30 mmol/L
Tris-HCl, pH 8.0, and 100 µmol/L phenylmethylsulfonyl
fluoride (1:9 wt/vol). After a 10-minute
centrifugation at 10 000g, the supernatant
was centrifuged for 60 minutes at 110 000g to
prepare microsomes, as described previously.23
The microsomes were resuspended in SDS-sample buffer and heated
to 100°C for 5 minutes, and the protein was separated on 8% SDS gels
under reducing conditions and transferred to Immobilon-P transfer
membranes (Millipore). The blots were blocked overnight with 100
mmol/L Tris-HCl, pH 7.4, containing 5% nonfat dry milk, 3%
albumin, and 0.5% Tween-20, followed by incubation for 16
hours with rabbit anti-murine polyclonal antiserum to COX-2 (Cayman) at
2.5 µg/mL dilution. The second reagent, biotinylated goat anti-rabbit
antibody, was detected with the use of avidin and biotinylated
horseradish peroxidase (Pierce) and exposed on film with the use of
enhanced chemiluminescence Western blotting detection reagents (ECL,
Amersham).
Statistical Analysis
All values are presented as mean±SEM. ANOVA, Bonferroni
t tests, and simple regression were used for statistical
analysis, and differences were considered significant at
P<0.05.
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Results |
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After coarctation, the wet weight of the left kidney of the vehicle-treated animals decreased and the right kidney increased, with a resultant ratio of left kidney weight/right kidney weight of 0.78±0.04 (n=10). Treatment with the COX-2–specific inhibitor SC58236 did not affect this alteration in kidney weight (0.79±0.06; n=9; P=NS compared with vehicle) but was different from control (1.02±0.02; n=9; P<0.01) (Figure 1).
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Renal cortical COX-2 expression was determined on day 7 after aortic coarctation. COX-2 mRNA expression in the affected left kidney, normalized to the housekeeping gene, GAPDH, was 180% of that in control animals (n=2), while COX-2 mRNA expression in the unaffected right kidney was 90% of control (Figure 2, top). Similarly, immunoreactive COX-2 protein expression was increased to 175% of control in the left kidney but was unchanged in the right kidney (n=2) (Figure 2, bottom). Of interest, treatment with the selective COX-2 inhibitor SC58236 partially blunted increases in COX-2 expression in the affected left kidney (Figure 2).
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On day 7 after surgery, PRA was significantly increased in the vehicle-treated coarcted rats compared with controls (control versus coarctation: 9.0±1.4 versus 84.6±6.5 ng Ang I per milliliter per hour; n=8 to 9; P<0.001). Treatment of coarcted rats with SC58236 significantly decreased PRA compared with the vehicle-treated animals (19.8±2.8 Ang I per milliliter per hour; n=9; P<0.01) (Figure 3, top). Renal renin activity was also measured in both affected (left) and unaffected (right) kidneys. Renin activity was significantly elevated in the left kidney after coarctation compared with control (189.0±28.6 versus 27.1±3.4 ng Ang I per hour per milligram protein; n=8 to 9; P<0.01) and was numerically but not statistically significantly decreased in the right kidney (23.4±1.8 ng Ang I per hour per milligram protein; P=NS). SC58236 treatment significantly decreased renin activity in the left kidney compared with the vehicle-treated rats (45.7±7.6 ng Ang I per hour per milligram protein; n=9; P<0.01), although the levels were still significantly greater than those of controls (P<0.01 compared with control). Right renal renin activity of SC58236-treated animals was unchanged (22.0±3.0 ng Ang I per hour per milligram protein; n=9; P=NS) (Figure 3, bottom).
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To determine whether alterations in renal renin mRNA expression coincided with the observed alterations in renal renin activity and PRA, RNA was extracted from each kidney and hybridized with a rat renin cDNA probe and normalized to GAPDH mRNA expression. In the vehicle-treated coarcted rats, renal renin mRNA increased in the left kidney (3.0±0.6-fold control; n=6; P<0.01), while renin mRNA in right kidney did not change significantly (1.1±0.1-fold control; P=NS). Administration of SC58236 decreased renin mRNA levels in the left kidney to 1.7±0.3-fold control (n=6; P<0.05 compared with untreated), without modifying expression in the right kidney (1.2±0.1-fold control; P=NS) (Figure 3, middle).
Seven days after surgery, aortic coarctation led to significant increases in carotid MAP compared with control animals (138±3 versus 87±2 mm Hg; n=9 to 11; P<0.01). Administration of SC58236 significantly decreased MAP compared with the vehicle-treated coarcted rats (122±5 mm Hg; n=14; P<0.05) (Figure 4, top). Regression analysis of the 3 groups of animals indicated a significant correlation between MAP and PRA (r=0.75, P<0.01) (Figure 4, bottom).
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Discussion |
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A role for prostaglandins in the mediation of hypertension has long been recognized, but initial observations concerning their potential mechanisms were somewhat contradictory. It is well recognized that in humans with essential hypertension, administration of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) can sometimes aggravate the hypertension.6 25 26 In contrast, chronic infusion of prostaglandin E1 in dogs led to renin-dependent hypertension.27 28 29 In dogs with significant renal artery stenosis, prostaglandin E2 production increased selectively from the stenotic kidney, and aspirin administration inhibited prostanoid synthesis and suppressed stimulation of renin release.30 In the aortic coarctation model of RVH in rats,5 the nonspecific cyclooxygenase inhibitor indomethacin also decreased PRA and decreased systemic blood pressure. Similarly, in humans with RVH, intravenous aspirin significantly reduced systemic blood pressure, while blood pressure was increased in patients with essential hypertension. Intravenous aspirin also decreased PRA in the subset of hyperreninemic essential hypertensives.6 Therefore, these data suggest that while NSAIDs may aggravate hypertension in non–renin-dependent hypertension, possibly by increasing salt retention, in renin-dependent hypertension, COX inhibition will decrease renin levels and ameliorate hypertension. The present studies demonstrate that similar effects are observed in RVH with selective inhibition of COX-2 activity and strongly suggest that the prostaglandins involved in regulation of increased renin production originate at least in part from the macula densa.
In the mammalian kidney, the macula densa consists of a cluster of morphologically unique tubular epithelial cells localized at the distal end of the thick ascending limb of Henle's loop. The macula densa participates in regulation of renin secretion and tubuloglomerular feedback.11 31 At low flow rates (functional volume depletion), sodium concentrations at the distal end of the ascending loop of Henle tubular fluid fall as low as 20 mEq/L, while at high flow rates, sodium concentrations may be as high as 60 to 80 mEq/L. By monitoring the salt concentration of the tubular fluid at the distal end of the loop of Henle, the macula densa thereby monitors glomerular filtration rate and absolute proximal reabsorption. Under physiological conditions, glomerular filtration rate and absolute proximal reabsorption are dependent on, and reflections of, effective circulating volume, and the macula densa is situated to serve as both a sensor and an effector of total salt and volume homeostasis; however, pathophysiological decreases in renal blood flow secondary to renal artery stenosis may also be sensed by the macula densa as a decrease in effective circulating volume. Although the underlying mechanisms for the elevated renin activity in these states were previously attributed solely to baroreceptor activation of renin,1 recent studies by Kurtz and associates7 8 have shown that macula densa–mediated renin release is also involved in mediating the increased renin expression in the 2-kidney, 1 clip model of RVH. In addition, these investigators have demonstrated an important role for prostanoids in mediating the increased renin expression in this model.3 7
In rat kidney, COX-2 expression is localized to scattered cTALH cells in the region of the macula densa, with occasional macula densa cells also expressing immunoreactive enzyme. In chronically salt-depleted animals, COX-2 expression in the macula densa and surrounding cTALH cells increases significantly.13 Recent studies in a 2-kidney, 1 clip model of RVH have also demonstrated increases in macula densa/cTALH cell expression of COX-2; in these studies, glomeruli with increased macula densa COX-2 expression also demonstrated increased juxtaglomerular renin expression.18 Similarly, in the present studies, aortic coarctation led to significant increases in renal cortical COX-2 mRNA and protein expression in the affected kidney, and selective inhibition of COX-2 significantly inhibited increases in PRA and renal renin activity and decreased renal renin mRNA expression. In addition, there was a partial but significant amelioration of the hypertension in response to COX-2 inhibition. As indicated in Figure 2, there also appeared to be a trend for SC58236 treatment to decrease COX-2 expression in the affected left kidney; further studies will be required to determine the mechanism underlying this observation.
In other studies in our laboratory, we have determined that administration of either an ACE inhibitor or an angiotensin type 1 receptor antagonist led to increases in macula densa and peri–macula densa COX-2 expression, suggesting that angiotensin II may downregulate cTALH/macula densa COX-2 expression. Furthermore, in rats treated with ACE inhibitors, elevations in plasma and kidney renin were significantly inhibited by simultaneous treatment with a selective COX-2 inhibitor, suggesting an important role for cTALH/macula densa–derived prostanoids in the regulation of renin release in response to inhibition of angiotensin II production.16 In similar studies, Harding et al17 have determined that administration of NS398, a selective COX-2 antagonist, significantly inhibited increases in renin mRNA expression and renal renin activity in response to a low salt diet. Therefore, these studies indicate that prostanoids generated from COX-2 localized in the region of the macula densa play an important role in both the physiological and pathophysiological regulation of renal renin expression and release.
In our previous studies, we demonstrated that SC58236 decreased prostaglandin production in isolated glomeruli from remnant kidneys.23 Therefore, although we assume that renal COX-2 activity in vivo was also inhibited, actual demonstration of inhibition is somewhat problematic, because the usually accepted means of determination of inhibition of renal cyclooxygenase activity, measurement of urinary prostaglandins, undoubtedly measures predominantly distal nephron (COX-1) activity.
During the early stages of experimental RVH (1 to 2 weeks after surgery), hypertension is renin dependent, and nonselective NSAIDs have been reported to ameliorate the hypertension when administered at this time.5 20 In contrast, at later times, the hypertension is not solely or even predominantly renin dependent, and nonselective NSAIDs either had no effect on blood pressure or actually exacerbated the hypertension,32 similar to the effect of NSAIDs in the deoxycorticosterone acetate/salt model of volume expansion hypertension.20 Of interest, however, when 8-week 2-kidney, 1 clip rats were placed on a sodium-deficient diet, indomethacin not only decreased PRA but also decreased blood pressure, suggesting an importance of the renin-angiotensin system in maintenance of hypertension in the face of salt restriction.32
There has been some discrepancy in the previously published literature concerning the effect of nonselective NSAIDs on renin secretion in models of RVH. A number of previous studies have indicated that nonselective NSAIDs (which inhibit both COX-1 and COX-2 at the concentrations used) decrease plasma renin in experimental RVH.5 20 However, unlike the findings of Jackson et al5 and Lin et al, 20 who both reported that 7 days after aortic coarctation, indomethacin decreased PRA, Schricker et al3 reported that 48 hours after unilateral renal artery clamp, increases in renin mRNA in the affected kidney were inhibited by both indomethacin and meclofenamate, but PRA was not significantly decreased. It should be noted, however, that there was a trend for decreases in both PRA and blood pressure with meclofenamate, which is a relatively equipotent inhibitor of both COX-1 and COX-2, with an IC50 for COX-2 of 9.7 µmol/L, but not with indomethacin, which has a reported IC50 for COX-2 of 100 to >1000 µmol/L.34 35
To date, published studies in humans have not localized renal cortical COX-2 to the macula densa region but to glomerular podocytes.35 However, studies with the relatively selective COX-2 inhibitors flosulide and meloxicam have found that these compounds inhibited furosemide-stimulated renin release in normal volunteers, suggesting that in humans COX-2 is also responsible for prostaglandin synthesis mediating renin release.36 37 In this regard, furosemide-stimulated renin release is thought to be mediated primarily by inhibition of macula densa Na/K/2Cl cotransport.38
In summary, the present studies indicate that in experimental RVH, administration of a selective inhibitor of COX-2 significantly decreased renal renin production and secretion. The decreases in plasma renin correlated with concomitant decreases in systemic blood pressure. These studies indicate that altered COX-2 expression may be an important mediator of renal renin generation under both physiological and pathophysiological conditions.
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Acknowledgments |
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This work was supported by the Vanderbilt George O'Brien Kidney and Urologic Diseases Center (National Institutes of Health grant DK 39261), by a grant from Searle Monsanto (St Louis, Mo), and by funds from the Department of Veterans Affairs.
Received November 17, 1998; first decision December 4, 1998; accepted February 18, 1999.
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  C. Y.-C. Peng, D. Sankaran, M. R. Ogborn, and H. M. Aukema Dietary Soy Protein Selectively Reduces Renal Prostanoids and Cyclooxygenases in Polycystic Kidney Disease Experimental Biology and Medicine, July 1, 2009; 234(7): 737 - 743. [Abstract] [Full Text] [PDF]
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 B. Neubauer, K. Machura, M. Chen, L. S. Weinstein, M. Oppermann, M. L. Sequeira-Lopez, R. A. Gomez, J. Schnermann, H. Castrop, A. Kurtz, et al. Development of vascular renin expression in the kidney critically depends on the cyclic AMP pathway Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1006 - F1012. [Abstract] [Full Text] [PDF]
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 Z. A. Radi Pathophysiology of Cyclooxygenase Inhibition in Animal Models Toxicol Pathol, January 1, 2009; 37(1): 34 - 46. [Abstract] [Full Text] [PDF]
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 L. M. Bivol, M. Hultstrom, O. A. Gudbrandsen, R. K. Berge, and B. M. Iversen Tetradecylthioacetic acid downregulates cyclooxygenase 2 in the renal cortex of two-kidney, one-clip hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1866 - R1873. [Abstract] [Full Text] [PDF]
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D. Z. I. Cherney, J. W. Scholey, R. Nasrallah, M. G. Dekker, C. Slorach, T. J. Bradley, R. L. Hebert, E. B. Sochett, and J. A. Miller Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type 1 diabetes mellitus Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1336 - F1341. [Abstract] [Full Text] [PDF]
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 D. Z.I. Cherney, J. A. Miller, J. W. Scholey, T. J. Bradley, C. Slorach, J. R. Curtis, M. G. Dekker, R. Nasrallah, R. L. Hebert, and E. B. Sochett The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes Diabetes, March 1, 2008; 57(3): 688 - 695. [Abstract] [Full Text] [PDF]
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 W. J. Welch, K. Patel, P. Modlinger, M. Mendonca, N. Kawada, K. Dennehy, S. Aslam, and C. S. Wilcox Roles of vasoconstrictor prostaglandins, COX-1 and -2, and AT1, AT2, and TP receptors in a rat model of early 2K,1C hypertension Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2644 - H2649. [Abstract] [Full Text] [PDF]
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D. Sankaran, N. Bankovic-Calic, M. R. Ogborn, G. Crow, and H. M. Aukema Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease Am J Physiol Renal Physiol, September 1, 2007; 293(3): F821 - F830. [Abstract] [Full Text] [PDF]
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C. Matzdorf, A. Kurtz, and K. Hocherl COX-2 activity determines the level of renin expression but is dispensable for acute upregulation of renin expression in rat kidneys Am J Physiol Renal Physiol, June 1, 2007; 292(6): F1782 - F1790. [Abstract] [Full Text] [PDF]
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F. Theilig, H. Debiec, B. Nafz, P. Ronco, R. Nusing, H. W. Seyberth, H. Pavenstadt, N. Bouby, and S. Bachmann Renal cortical regulation of COX-1 and functionally related products in early renovascular hypertension (rat) Am J Physiol Renal Physiol, November 1, 2006; 291(5): F987 - F994. [Abstract] [Full Text] [PDF]
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M. C. Chappell, L. M. Yamaleyeva, and B. M. Westwood Estrogen and salt sensitivity in the female mRen(2).Lewis rat Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1557 - R1563. [Abstract] [Full Text] [PDF]
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 M.-Z. Zhang, B. Yao, H.-F. Cheng, S.-W. Wang, T. Inagami, and R. C. Harris Renal cortical cyclooxygenase 2 expression is differentially regulated by angiotensin II AT1 and AT2 receptors PNAS, October 24, 2006; 103(43): 16045 - 16050. [Abstract] [Full Text] [PDF]
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L. Warford-Woolgar, C. Y.-C. Peng, J. Shuhyta, A. Wakefield, D. Sankaran, M. Ogborn, and H. M. Aukema Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys Am J Physiol Renal Physiol, April 1, 2006; 290(4): F897 - F904. [Abstract] [Full Text] [PDF]
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 R. C. Harris and M. D. Breyer Update on Cyclooxygenase-2 Inhibitors Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 236 - 245. [Abstract] [Full Text] [PDF]
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U. G. Friis, J. Stubbe, T. R. Uhrenholt, P. Svenningsen, R. M. Nusing, O. Skott, and B. L. Jensen Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells Am J Physiol Renal Physiol, November 1, 2005; 289(5): F989 - F997. [Abstract] [Full Text] [PDF]
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 J. D. Imig, X. Zhao, C. Z. Zaharis, J. J. Olearczyk, D. M. Pollock, J. W. Newman, I.-H. Kim, T. Watanabe, and B. D. Hammock An Orally Active Epoxide Hydrolase Inhibitor Lowers Blood Pressure and Provides Renal Protection in Salt-Sensitive Hypertension Hypertension, October 1, 2005; 46(4): 975 - 981. [Abstract] [Full Text] [PDF]
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F. Schweda, F. Segerer, H. Castrop, J. Schnermann, and A. Kurtz Blood Pressure-Dependent Inhibition of Renin Secretion Requires A1 Adenosine Receptors Hypertension, October 1, 2005; 46(4): 780 - 786. [Abstract] [Full Text] [PDF]
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R. C. Hermida, D. E. Ayala, C. Calvo, J. E. Lopez, A. Mojon, M. Rodriguez, and J. R. Fernandez Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives Hypertension, October 1, 2005; 46(4): 1060 - 1068. [Abstract] [Full Text] [PDF]
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 R. C. Hermida, D. E. Ayala, C. Calvo, and J. E. Lopez Aspirin Administered at Bedtime, But Not on Awakening, Has an Effect on Ambulatory Blood Pressure in Hypertensive Patients J. Am. Coll. Cardiol., September 20, 2005; 46(6): 975 - 983. [Abstract] [Full Text] [PDF]
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F. Schweda, J. Klar, S. Narumiya, R. M. Nusing, and A. Kurtz Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys Am J Physiol Renal Physiol, September 1, 2004; 287(3): F427 - F433. [Abstract] [Full Text] [PDF]
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F. Schweda, M. Kammerl, C. Wagner, B. K. Kramer, and A. Kurtz Upregulation of macula densa cyclooxygenase-2 expression is not dependent on glomerular filtration Am J Physiol Renal Physiol, July 1, 2004; 287(1): F95 - F101. [Abstract] [Full Text] [PDF]
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A. Paliege, D. Mizel, C. Medina, A. Pasumarthy, Y. G. Huang, S. Bachmann, J. P. Briggs, J. B. Schnermann, and T. Yang Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E2 Am J Physiol Renal Physiol, July 1, 2004; 287(1): F152 - F159. [Abstract] [Full Text] [PDF]
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H.-F. Cheng and R. C. Harris Cyclooxygenases, the Kidney, and Hypertension Hypertension, March 1, 2004; 43(3): 525 - 530. [Abstract] [Full Text] [PDF]
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D. Song, E. Arikawa, D. Galipeau, M. Battell, and J. H. McNeill Androgens Are Necessary for the Development of Fructose-Induced Hypertension Hypertension, March 1, 2004; 43(3): 667 - 672. [Abstract] [Full Text] [PDF]
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J. Stubbe, B. L. Jensen, S. Bachmann, P. Morsing, and O. Skott Cyclooxygenase-2 contributes to elevated renin in the early postnatal period in rats Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2003; 284(5): R1179 - R1189. [Abstract] [Full Text] [PDF]
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A. Hartner, N. Cordasic, M. Goppelt-Struebe, R. Veelken, and K. F. Hilgers Role of macula densa cyclooxygenase-2 in renovascular hypertension Am J Physiol Renal Physiol, March 1, 2003; 284(3): F498 - F502. [Abstract] [Full Text] [PDF]
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H. Castrop, J. Klar, C. Wagner, K. Hocherl, and A. Kurtz General inhibition of renocortical cyclooxygenase-2 expression by the renin-angiotensin system Am J Physiol Renal Physiol, March 1, 2003; 284(3): F518 - F524. [Abstract] [Full Text] [PDF]
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 H.-F. Cheng and R. C. Harris Cyclooxygenase-2 Expression in Cultured Cortical Thick Ascending Limb of Henle Increases in Response to Decreased Extracellular Ionic Content by Both Transcriptional and Post-transcriptional Mechanisms. ROLE OF p38-MEDIATED PATHWAYS J. Biol. Chem., November 15, 2002; 277(47): 45638 - 45643. [Abstract] [Full Text] [PDF]
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 A. Ollerstam and A.E. G Persson Macula densa neuronal nitric oxide synthase Cardiovasc Res, November 1, 2002; 56(2): 189 - 196. [Abstract] [Full Text] [PDF]
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H.-F. Cheng, S.-W. Wang, M.-Z. Zhang, J. A. McKanna, R. Breyer, and R. C. Harris Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1 Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R638 - R646. [Abstract] [Full Text] [PDF]
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W. H. Beierwaltes Cyclooxygenase-2 products compensate for inhibition of nitric oxide regulation of renal perfusion Am J Physiol Renal Physiol, July 1, 2002; 283(1): F68 - F72. [Abstract] [Full Text] [PDF]
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 H. Castrop, H. Vitzthum, K. Schumacher, F. Schweda, and A. Kurtz Low Tonicity Mediates a Downregulation of Cyclooxygenase-1 Expression by Furosemide in the Rat Renal Papilla J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1136 - 1144. [Abstract] [Full Text] [PDF]
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M. Kitahara, F. Eitner, T. Ostendorf, U. Kunter, U. Janssen, R. Westenfeld, K. Matsui, D. Kerjaschki, and J. Floege Selective Cyclooxygenase-2 Inhibition Impairs Glomerular Capillary Healing in Experimental Glomerulonephritis J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1261 - 1270. [Abstract] [Full Text] [PDF]
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F. Theilig, V. Campean, A. Paliege, M. Breyer, J. P. Briggs, J. Schnermann, and S. Bachmann Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex Hypertension, April 1, 2002; 39(4): 848 - 853. [Abstract] [Full Text] [PDF]
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 J. Schnermann Cyclooxygenase-2 and macula densa control of renin secretion Nephrol. Dial. Transplant., September 1, 2001; 16(9): 1735 - 1738. [Full Text] [PDF]
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R. C. Harris and M. D. Breyer Physiological regulation of cyclooxygenase-2 in the kidney Am J Physiol Renal Physiol, July 1, 2001; 281(1): F1 - F11. [Abstract] [Full Text] [PDF]
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H. CASTROP, F. SCHWEDA, K. SCHUMACHER, K. WOLF, and A. KURTZ Role of Renocortical Cyclooxygenase-2 for Renal Vascular Resistance and Macula Densa Control of Renin Secretion J. Am. Soc. Nephrol., May 1, 2001; 12(5): 867 - 874. [Abstract] [Full Text]
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H.-F. Cheng, J.-L. Wang, M.-Z. Zhang, S.-W. Wang, James. A. McKanna, and R. C. Harris Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition Am J Physiol Renal Physiol, March 1, 2001; 280(3): F449 - F456. [Abstract] [Full Text] [PDF]
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B. Mann, A. Hartner, B. L. Jensen, K. F. Hilgers, K. Hocherl, B. K. Kramer, and A. Kurtz Acute upregulation of COX-2 by renal artery stenosis Am J Physiol Renal Physiol, January 1, 2001; 280(1): F119 - F125. [Abstract] [Full Text] [PDF]
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R. C. HARRIS Cyclooxygenase-2 in the Kidney J. Am. Soc. Nephrol., December 1, 2000; 11(12): 2387 - 2394. [Full Text]
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T. Yang, Y. Endo, Y. G. Huang, A. Smart, J. P. Briggs, and J. Schnermann Renin expression in COX-2-knockout mice on normal or low-salt diets Am J Physiol Renal Physiol, November 1, 2000; 279(5): F819 - F825. [Abstract] [Full Text] [PDF]
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R. C. Harris Macula densa signalling--a potential role of cyclooxygenase-2 (COX-2)? Nephrol. Dial. Transplant., October 1, 2000; 15(10): 1504 - 1506. [Full Text] [PDF]
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F. Rodriguez, M. T. Llinas, J. D. Gonzalez, J. Rivera, and F. J. Salazar Renal Changes Induced by a Cyclooxygenase-2 Inhibitor During Normal and Low Sodium Intake Hypertension, August 1, 2000; 36(2): 276 - 281. [Abstract] [Full Text] [PDF]
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T. Yang, J. M. Park, L. Arend, Y. Huang, R. Topaloglu, A. Pasumarthy, H. Praetorius, K. Spring, J. P. Briggs, and J. Schnermann Low Chloride Stimulation of Prostaglandin E2 Release and Cyclooxygenase-2 Expression in a Mouse Macula Densa Cell Line J. Biol. Chem., November 22, 2000; 275(48): 37922 - 37929. [Abstract] [Full Text] [PDF]
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H. Tokuyama, K. Hayashi, H. Matsuda, E. Kubota, M. Honda, K. Okubo, Y. Ozawa, and T. Saruta Stenosis-dependent role of nitric oxide and prostaglandins in chronic renal ischemia Am J Physiol Renal Physiol, May 1, 2002; 282(5): F859 - F865. [Abstract] [Full Text] [PDF]
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K. Hocherl, M. Kammerl, F. Kees, B. K. Kramer, H. F. Grobecker, and A. Kurtz Role of renal nerves in stimulation of renin, COX-2, and nNOS in rat renal cortex during salt deficiency Am J Physiol Renal Physiol, March 1, 2002; 282(3): F478 - F484. [Abstract] [Full Text] [PDF]
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