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CARDIOVASCULAR
Department of Pharmacology, New York Medical College, Valhalla, New York
Received August 31, 2004; accepted May 5, 2005.
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Abstract |
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from the isolated perfused kidney was used as an index of COX activity, and Western analysis was used to determine COX-2 protein expression. In untreated diabetic rats, the release of prostaglandins in response to AA was markedly enhanced; the increase in release of both 6-ketoPGF1 and PGE2 after AA was twice that in control rats. Renal cortical COX-2 expression in diabetic rats was 3-fold that of control rats. Tempol treatment reduced the AA-stimulated release of prostaglandins to levels seen in control rats; this was associated with reduced expression of COX-2 protein to levels not different from that in control rats. However, the enhanced vasoconstrictor response to AA in diabetic rats was unaffected by tempol treatment but abolished by inhibition of COX-1 with SC58560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole]. The addition of tempol to the perfusate of kidneys from diabetic and control rats had only a slight effect on prostaglandin release. We conclude that oxidative stress is an integral component of the mechanism involved in the induction of renal COX-2 in diabetes.
; Quilley and McGiff, 1985; Schambelan et al., 1985). Craven et al. (1987) linked these changes to the increased GFR observed in diabetes by showing that inhibition of COX with indomethacin reduced GFR in diabetic but not in control rats. However, most of these studies were conducted before the recognition and characterization of multiple COX isoforms. Recent studies indicate that COX-2 may contribute to the increased formation of renal prostaglandins in the diabetic rat and that these may play a role in the renal functional consequences. Thus, Komers et al. (2001) reported increased renal cortical expression of COX-2 and found that administration of a COX-2 inhibitor reduced GFR in streptozotocin (STZ)-diabetic rats treated with insulin. Harris' group reported that chronic administration of a COX-2 inhibitor to hypertensive diabetic rats reduced the appearance of markers for renal damage, suggesting that increased COX-2 may be an early step in the development of nephropathy (Cheng et al., 2002). We confirmed the increase in the renal cortical expression of COX-2 in untreated STZ-diabetic rats and showed that a COX-2 inhibitor reduced the enhanced endoperoxide-mediated renal vasoconstrictor response to AA as well as the enhanced associated release of prostaglandins that we had reported for the diabetic rat (Quilley and McGiff, 1990; Quilley and Chen, 2003).
The stimulus for induction of COX-2 in diabetes is likely hyperglycemia, which has been shown to increase oxidative stress in a variety of cells, including endothelial cells and mesangial cells (Catherwood et al., 2002; Cosentino et al., 2003). Moreover, diabetes is well recognized as a condition of oxidative stress, and reactive oxygen species such as superoxide have been shown to induce COX-2 (Cosentino et al., 2003; Kiritoshi et al., 2003). However, the role of oxidative stress and superoxide in the induction of renal COX-2 in diabetes has not been addressed, the primary aim of the studies reported here. Consequently, we addressed the effects of chronic administration of the superoxide dismutase mimetic tempol on the induction of renal COX-2 in the STZ-diabetic rat. Renal release of prostaglandins in response to AA was used as an index of COX activity, although it does not distinguish the activity of COX-2 from COX-1. The results confirmed those of our previous study showing increased renal expression of COX-2, which was associated with increased release of prostaglandins in response to AA in the diabetic rat. In addition, the renal vasoconstrictor effect of AA, which is COX-dependent and mediated via endoperoxides (Quilley et al., 1989), was enhanced in the diabetic rat. Treatment with tempol to reduce superoxide prevented the increased renal expression of COX-2 and reduced AA-stimulated release of prostaglandins in the diabetic rat, but it did not influence the enhanced vasoconstrictor effect of AA.
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Materials and Methods |
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) used tempol at approximately 30 mg/kg/day and showed that it reduced urinary excretion of isoprostanes in both control and endothelin-treated rats. The dose that we used is comparable with that used by Nassar et al. (2002) who reported that tempol treatment abolished the increase in vascular superoxide and isoprostane formation in diabetic rats. The second group of diabetic rats and the control group received no treatment. Twenty-eight days later, rats were anesthetized with pentobarbitone (65 mg/kg i.p.), and the kidney was prepared for perfusion. Briefly, after a midline laparotomy, the right renal artery was cannulated via the mesenteric artery to avoid interruption of blood flow, and the kidney was removed from the rat and perfused with oxygenated Krebs-Henseleit buffer at 37°C at constant flow, which was adjusted to obtain a perfusion pressure of 60 to 90 mm Hg. Glucose levels in tail vein blood were determined with a glucometer (Ames, Elkhart, IN). The left kidney was removed for determination of renal cortical COX-2 protein expression.
After at least a 10-min perfusion and once a stable perfusion pressure was obtained, vasoconstrictor responses to 0.3, 1, and 3 µg of AA were determined. Responses to a single dose of angiotensin II (10 ng) were also determined. Perfusate samples were collected for 1min before and 1 min after the 3-µg dose of AA to determine prostaglandin release.
In another series of experiments to address the acute effects of tempol on renal AA responses and prostaglandin release, we used diabetic and control rats 8 to 10 weeks after the induction of diabetes with STZ or treatment with vehicle, respectively. The kidneys were isolated and perfused with Krebs' buffer containing 500 µM tempol or vehicle (water), and perfusion pressure responses to 1, 3, and 10 µg of AA were determined. Samples for prostaglandin release were obtained as described above. The doses of AA chosen were higher than those in the previous experiments because these rats were slightly older (15–17 weeks), and sensitivity to the vasoconstrictor effects of AA declines with age (Quilley and McGiff, 1990). However, regardless of age, the diabetic rat kidney exhibits an exaggerated response to AA compared with age-matched control rats.
In another series of experiments, we tested the effects of a selective inhibitor of COX-1 on the renal vasoconstrictor effects of AA and the associated release of prostaglandins. Rats with diabetes of 4- to 6-week duration and age-matched control rats were used. The isolated kidney was prepared as described above, and the COX-1 inhibitor SC58560, which was a gift from Pfizer, Inc. (New York, NY), was added to the perfusate at a concentration of 5 x 10-8 M, which is almost 20 times the IC50 value for recombinant COX-1 and almost 100 times less than the IC50 for recombinant COX-2 (Smith et al., 1998). At least 15 min was allowed before responses to 1 and 3 µg of AA were determined. Responses to 100 ng of phenylephrine were also tested to determine any effects of the inhibitor in reducing vasoconstrictor responsiveness.
Prostaglandin Measurements. One-minute perfusate collections were made immediately before and after the administration of 3 µg of AA for the measurement of PGE2 and 6-ketoPGF1 as an index of cyclooxygenase activity. Levels of the two prostanoids in the renal perfusates were determined by enzyme immunoassay using kits obtained from Cayman Chemical (Ann Arbor, MI). 6-KetoPGF1 was chosen as an index of conversion of AA by the endothelium, the presumed site of generation of endoperoxides, whereas PGE2 levels were determined as an index of total renal prostaglandin formation.
Urinary Isoprostane Excretion. Another group of rats with diabetes of 5-week duration was compared with age-matched control group rats for urinary isoprostane excretion. Rats were placed in metabolism cages, and 24-h urine was collected. 8-Isoprostane PGF2 was measured using an enzyme immunoassay (Cayman Chemical). Unpurified samples were diluted in enzyme immunoassay buffer for assay.
Western Blot. The cortex was homogenized in radioimmunoprecipitation assay buffer and subjected to centrifugation at 10,000 and 14,000 rpm. The protein in the supernatant was determined using a Bio-Rad assay kit, and 50 µg was mixed with 5x SDS-polyacrylamide gel electrophoresis sample buffer (500 mM dithiothreitol, 0.2% bromphenol blue, and 50% glycerol) and boiled for 3 min. Proteins were separated on a 10% SDS-polyacrylamide gel electrophoresis gel, transferred to a nitrocellulose membrane, and immunoblotted with a rabbit anti-mouse COX-2 polyclonal antibody (1:1000 dilution; Cayman Chemical). Membranes were washed with Tris-buffered saline containing Tween 20 and incubated with horseradish peroxidase-conjugated antisera. COX-2 protein was then detected by enhanced chemiluminescence.
Analysis of Data. All data are expressed as means ± S.E.M. and were compared using an unpaired t test or analysis of variance in which individual points were compared using a modified t-statistic (Bonferroni). A value of p < 0.05 was considered statistically significant.
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Results |
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For the isolated perfused kidney preparations, there were no differences in basal perfusion pressure among the various groups: 73 ± 4, 68 ± 2, and 67 ± 2 mm Hg in citrate, diabetic, and diabetic plus tempol groups, respectively. However, perfusate flow rates were higher in the two diabetic groups, 15 ± 1.4 ml/min for the untreated group and 16 ± 1.4 ml/min for the tempol-treated group, compared with 10.8 ± 0.4 ml/min for the control group.
The release of PGE2 and 6-ketoPGF1 from control, diabetic, and tempol-treated diabetic rat kidneys before and after 3 µg of AA is shown in Figs. 1 and 2. Basal release of PGE2 at the beginning of the perfusion was less in the diabetic groups than the control group. In the untreated diabetic group, PGE2 release was 883 ± 99 pg/min compared with 611 ± 77 pg/min for the tempol-treated diabetic group and 1481 ± 412 pg/min for the control group. These differences became more apparent with time of perfusion and after administration of AA. There were no differences between the groups in terms of basal release of 6-ketoPGF1 at the beginning of the perfusion. However, release before the administration of 3 µg of AA was significantly less in the tempol-treated diabetic group compared with the untreated diabetic and control groups (Fig. 2). After administration of AA, release of both PGE2 and 6-ketoPGF1 was greater in the untreated diabetic group compared with the control group (Figs. 1 and 2). In contrast, tempol treatment of diabetic rats for 28 days reduced the enhanced release of PGE2 and 6-ketoPGF1 observed in the untreated diabetic group, so there were no differences from the control group.
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-actin, in control, diabetic, and tempol-treated diabetic rat kidneys. As we reported above, diabetes leads to increased renal COX-2 expression, which corresponds to increased release of prostaglandins stimulated by AA. Tempol treatment of diabetic rats for 28 days prevented the increase in COX-2 expression in the diabetic rat kidney so that levels were similar to those in the control group, also consistent with the effects of tempol on AA-stimulated prostaglandin release.
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Administration of bolus doses of AA to the perfused kidney resulted in dose-dependent vasoconstrictor responses that were markedly enhanced in kidneys from diabetic rats (Fig. 4). Treatment of diabetic rats with tempol for 28 days did not modify the enhanced vasoconstrictor effects of AA (Fig. 4). We also determined the response to a bolus dose of 10 ng of angiotensin II in four of the five kidneys from each group of rats. The response was much greater in the untreated diabetic group compared with the control group, 138 ± 12 versus 36 ± 12 mm Hg (p < 0.01). Tempol treatment of diabetic rats moderated the enhanced vasoconstrictor effect of angiotensin II to 81 ± 13 mm Hg.
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Because tempol treatment of diabetic rats prevented the increased expression of COX-2 and the enhanced release of AA-stimulated prostaglandins, we conducted another series of experiments to determine the acute effects of tempol on AA-stimulated prostaglandin release from the isolated kidney to determine whether tempol affected COX activity. Thus, tempol was added to the perfusing solution at a concentration of 500 µM. As before, perfusate flow rates were slightly higher in the diabetic rat kidneys compared with control rat kidneys; 15.6 ± 0.6 ml/min for the untreated diabetic group, 14.9 ± 0.5 ml/min for the tempol-treated diabetic group, 13.0 ± 0.7 ml/min for the untreated control group, and 12.9 ± 0.4 ml/min for the tempol-treated citrate group, which produced perfusion pressures of 64 ± 5, 63 ± 2, 66 ± 3, and 71 ± 2 mm Hg, respectively. Figure 5 shows the release of 6-ketoPGF1 before and after 3 µg of AA in the various groups. Confirming the previous studies, basal release was not different between the diabetic and control group and was unaffected by tempol. However, AA-stimulated release of 6-ketoPGF1 was greatly enhanced in the diabetic rat kidney compared with the control. Tempol was without influence on AA-stimulated release in the control group but resulted in a slight reduction in the diabetic group. The release of PGE2 followed a similar trend to that of the previous studies, i.e., basal release was reduced in the diabetic rat, whereas AA-stimulated release was enhanced. Neither basal nor stimulated PGE2 release was affected by tempol (data not shown). As before, the renal vasoconstrictor effect of AA was greatly enhanced in the diabetic versus the control rat. For example, 3 µg of AA increased perfusion pressure by 191 ± 30 mm Hg in the diabetic rat kidney (n = 3) compared with 37 ± 12 mm Hg in the control (n = 4). Acute administration of tempol to the kidneys did not modify the vasoconstrictor effect of AA in either the diabetic (n = 4) or control group (n = 4), 207 ± 19 and 30 ± 6 mm Hg, respectively.
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Discussion |
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STZ-induced diabetes increases the renal expression of COX-2 protein (Komers et al., 2001; Quilley and Chen, 2003). We showed that the increase in COX-2 expression was associated with increased release of prostaglandins from the kidney challenged with AA as well as enhanced vasoconstrictor responses to AA (Quilley and Chen, 2003). We suggested that COX-2 contributed to both of these manifestations of experimental diabetes because an inhibitor of COX-2 reduced the vasoconstrictor effects of the lower doses of AA only in the diabetic rat kidney and also reduced the release of prostaglandins. The present study provides evidence for oxidative stress associated with diabetes as the stimulus for induction of COX-2 because tempol completely prevented the increase in COX-2 expression in diabetic rats, which exhibit increased oxidative stress using urinary isoprostane excretion as a marker. This is consistent with in vitro studies demonstrating that oxidative stress increases COX-2 protein expression in a variety of cells (Cosentino et al., 2003; Kiritoshi et al., 2003) and that exposure of cells to elevated glucose levels increased superoxide formation and oxidative stress (Catherwood et al., 2002; Cosentino et al., 2003). However, this is the first study that links hyperglycemia, oxidative stress, and induction of COX-2 in vivo. We assume that hyperglycemia associated with the diabetic state leads to oxidative stress that, in turn, results in the induction of COX-2. Nonetheless, we cannot exclude some other manifestation of the diabetic state as a contributory factor to the induction of COX-2. Because COX-2 has been linked to renal damage in models of diabetes by showing that inhibition of COX-2 reduced the expression of markers of renal injury in a hypertensive diabetic rat model and that a PGE receptor antagonist also reduced renal injury (Cheng et al., 2002; Makino et al., 2002), prevention of induction of COX-2 with tempol could be expected to ameliorate the renal complications of diabetes. It would be of great interest to maintain diabetic rats on tempol and determine the progress of renal injury. If hyperglycemia is the initial stimulus for the induction of COX-2, then the effects should not be limited to the kidney but to all other cells exposed to the diabetic milieu, particularly endothelial cells of blood vessels.
Because AA elicits COX-dependent, endoperoxide-mediated vasoconstrictor responses in the rat kidney that are associated with release of prostaglandins, we sought to use these an indices of COX activity. In the diabetic rat kidney, both the enhanced vasoconstrictor effect of AA and the increased release of prostaglandins corresponded with increased expression of COX-2. However, treatment with tempol, which prevented the increased expression of COX-2 revealed dissociation between the vasoconstrictor response to AA and the release of prostaglandins. Tempol treatment reduced AA-stimulated prostaglandin release without modifying the vasoconstrictor effect of AA. A similar dissociation was seen in our previous study where inhibition of COX-2 with nimesulide in control rat kidneys reduced AA-stimulated release of prostaglandins but did not modify the vasoconstrictor effect of AA in contrast to what was observed in diabetic rat kidneys (Quilley and Chen, 2003). However, we cannot entirely exclude an effect of nimesulide on COX-1. Because of this discrepancy, we conducted experiments with a selective inhibitor of COX-1, which almost abolished the renal vasoconstrictor effect of AA in both diabetic and control rat kidneys. This effect could not be attributed to a generalized decrease in vasoconstrictor responsiveness because responses to phenylephrine were unaffected. These results indicate that COX-1 is the isoform responsible for the generation of prostanoids that elicit renal vasoconstriction in response to AA, although we cannot exclude an effect of the inhibitor, which abolished AA-stimulated prostaglandin release, on COX-2. These observations are difficult to explain in light of our previous studies showing that inhibitors of COX-2 reduced prostaglandin release and vasoconstrictor responses to AA in the diabetic rat kidney but failed to modify the vasoconstrictor effect of AA in control rat kidneys. If nimesulide exerted an inhibitory effect on COX-1, vasoconstrictor responses to AA should also be reduced in control rat kidneys, which was not the case. We have no explanation for this discrepancy. Based on the present study, COX-1 is the isoform responsible for the conversion of AA to the endoperoxides in the renal vasculature of both nondiabetic rats and diabetic rats, and an increase in expression or activity could account for the increased vasoconstrictor responses to AA. COX-2 is expressed constitutively at several sites in the kidney (Harris et al., 1994; Davidge, 2001) where it presumably contributes to the formation of prostaglandins in response to AA given intravascularly. However, in the diabetic kidney, it is possible that infiltration of inflammatory cells contribute to the increase in COX-2. We cannot assume that prostaglandin release from the perfused kidney is derived solely from the vasculature, which is the site of action for the vasoconstrictor effect of endoperoxides, formed as the result of activity of COX-1. It would seem likely that the vasculature is one of several sources of prostaglandins produced by the kidney in response to AA; therefore, release in response to AA may not always be expected to correlate with vasoconstrictor activity. Moreover, differences in vasoconstrictor responsiveness to endoperoxides in diabetic versus control rat kidneys could also explain increased vasoconstrictor responsiveness to AA in the absence of increased production in the diabetic rat. We have shown that renal vasoconstrictor responses to U46619
[GenBank]
, an endoperoxide analog, are enhanced in the diabetic rat (Quilley and McGiff, 1990). Consequently, vasoconstrictor responses to AA do not necessarily provide a good index of COX activity. However, release of prostaglandins in response to AA is a useful index of renal COX activity, but it does not provide information on the site of increased expression/activity of COX. Immunohistochemical analysis of COX-1 and COX-2 is required to determine the sites of increased COX-2 expression.
The observation that tempol treatment reduced AA-stimulated prostaglandin release in conjunction with reduced renal expression of COX-2 suggests that COX-2 contributes to the formation of prostaglandins in the diabetic rat kidney. However, it is also possible that tempol, by reducing oxygen-derived free radicals, may have a direct effect on COX activity, which requires the presence of hydroperoxides for catalytic activity (Davidge, 2001). We addressed this possibility by testing the acute effects of tempol, added to the renal perfusate, on responses to AA and by measuring the release of prostaglandins. In samples obtained immediately before the administration of AA, tempol was without effect on prostaglandin release from either control or diabetic rat kidneys. This is in contrast to chronic administration of tempol to diabetic rats where basal renal release of prostaglandins was decreased compared with untreated diabetic rats. However, treatment of diabetic rat kidneys with tempol had a slight inhibitory effect on AA-stimulated prostaglandin, achieving significance with 6-ketoPGF1. These results indicate that tempol may influence the activity of COX when it is maximally stimulated and could account, in part, for the diminished AA-stimulated prostaglandin release in kidneys of diabetic rats treated with tempol for 28 days, assuming that tempol remains within the cells after perfusion of the kidney is started.
The mechanism whereby diabetes-induced oxidative stress increases the renal expression of COX-2 was not addressed in this study and awaits future investigation. Protein kinase C has been invoked, but it is not clear whether hyperglycemia-induced activation of this kinase leads to oxidative stress or whether oxidative stress increases the activity of protein kinase C (Nishikawa et al., 2000; Whiteside and Dlugosz, 2002). Similarly, induction of COX-2 in response to cytokines and lipopolysaccharide, which stimulates the production of cytokines, involves oxidative stress (Feng et al., 1995). Because a feature of diabetes is altered cytokine formation (Kalantarinia et al., 2003), the sequence of events remains to be clarified. The results of this study do not mean that superoxide is the mediator of COX-2-induction, only that is plays a central role. Thus, NO formation is also increased in the diabetic kidney (Sugimoto et al., 1998; Cosenzi et al., 2002; Onozato et al., 2002), and its product upon reaction with superoxide, i.e., peroxynitrite, has also been reported to induce COX-2 (Eligini et al., 2001; Nedelec et al., 2001). That peroxynitrite formation is increased in diabetes is apparent from increased staining for nitrotyrosine (Thuraisingham et al., 2000; Onozato et al., 2002), and preliminary data from our laboratory showing increased renal expression of nitrotyrosine support these results.
In summary, this study shows that the induction of renal COX-2 in diabetes can be prevented by tempol treatment, which coincidentally reduces AA-stimulated prostaglandin release from the kidney without modifying the vasoconstrictor effect of AA, which seems to be solely dependent on COX-1 activity. The results with tempol, therefore, suggest a role of superoxide, which is increased by diabetes and hyperglycemia, in the induction of COX-2.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: AA, arachidonic acid; COX, cyclooxygenase; GFR, glomerular filtration rate; STZ, streptozotocin; SC58560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; PG, prostaglandin; U46619
[GenBank]
, 9,11-dideoxy-9,11-methanoepoxy PGF2.
Address correspondence to: Dr. John Quilley, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail: john_quilley{at}nymc.edu
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Z. Guo, Z. Xia, J. Jiang, and J. H. McNeill Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-L-cysteine Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1728 - H1736. [Abstract] [Full Text] [PDF]
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