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CARDIOVASCULAR
Department of Pharmacology, New York Medical College, Valhalla, New York
Received July 25, 2007; accepted November 8, 2007.
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Abstract |
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agonist on renal COX-2 expression as fibrates exert renal protective effects. Forty-eight hours after the induction of diabetes with streptozotocin in male Wistar rats, fenofibrate treatment (100 mg/kg/day) was started, and the effects were compared with untreated diabetic rats and treated and untreated age-matched control rats (n = 5 per group). After 12 to 14 weeks of treatment, the right kidney was perfused to determine prostaglandin release in response to arachidonic acid (AA), and the left kidney was used to examine the expression of COX-2 and nitrotyrosine, an index of ONOO formation. Release of prostaglandin (PG) E2 in response to AA was enhanced in the diabetic rat kidney compared with control (4.8 ± 0.7 versus 1.9 ± 0.7 ng/min) and reduced by fenofibrate to 0.6 ± 0.2 ng/min. A similar pattern was obtained for AA-stimulated release of 6-ketoPGF1. The effects of fenofibrate were associated with reduced renal expression of COX-2 and nitrotyrosine in diabetic rats. We used creatinine clearance as an index of GFR, which was increased in the diabetic rat, 3.09 ± 0.4 versus 1.15 ± 0.1 ml/min for control, and reduced by fenofibrate treatment to 1.87 ± 0.3 ml/min. These results show that fenofibrate treatment of diabetic rats decreases renal COX-2 expression, possibly by reducing nitrosative stress, and is associated with a reduction of the enhanced GFR.
; Quilley et al., 1985; Schambelan et al., 1985). For the most part, these studies showed an increase in COX activity and prostaglandin release from the kidney, mesangial cells, and glomeruli of diabetic rats (Kreisberg and Patel, 1983; Quilley and McGiff, 1985; Schambelan et al., 1985). The derangements in renal AA metabolism have been linked to hyperfiltration of early diabetes as nonsteroidal anti-inflammatory drugs reduce GFR (Craven et al., 1987; Moel et al., 1987). However, most of these studies were conducted before the recognition and characterization of multiple COX isoforms; recently, increased expression of COX-2 has been demonstrated in diabetes (Komers et al., 2001; Quilley and Chen, 2003) and has also been linked to hyperfiltration (Komers et al., 2001). These 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 manifestations of the condition. 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-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 release of prostaglandins (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 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). We recently reported that chronic administration of the superoxide dismutase mimetic, Tempol, prevented the induction of renal COX-2 in the STZ-diabetic rat and decreased the enhanced renal release of prostaglandins in response to AA, suggesting that superoxide plays a central role in the induction of COX-2 in the diabetic rat (Li et al., 2005). We, subsequently, showed that chronic inhibition of NOS with N
-nitro-L-arginine methyl ester prevented the up-regulation of renal cortical COX-2 and the associated increased release of prostaglandins in response to AA (Chen et al., 2006). Taken together, these results suggest a role for peroxynitrite as a contributory stimulus for the up-regulation of COX-2 in diabetes. Accordingly, peroxynitrite generation is increased in both human (Thuraisingham et al., 2000; Szabó et al., 2002) and experimental diabetes (Onozato et al., 2002), and peroxynitrite has been shown to increase COX-2 expression in endothelial cells (Eligini et al., 2001).
PPAR agonists such as the fibrates have been shown to have renoprotective effects and to exert a wide range of activities including a reduction of oxidative stress (Inoue et al., 2001) and anti-inflammation (van Raalte et al., 2004), possibly by increasing I
B to inhibit the activation of NFB (Cernuda-Morollón et al., 2002), which is likely to be an obligatory step in the induction of COX-2. Consequently, activation of PPAR might be expected to interfere in the up-regulation of COX-2. We hypothesized that treatment of diabetic rats with fenofibrate would reduce renal COX-2 expression and the associated increase in renal prostaglandin release and, thereby, ameliorate the hyperfiltration.
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Materials and Methods |
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Isolated Perfused Kidney. Following pentobarbital anesthesia (65 mg/kg i.p.), the right renal artery was cannulated via the mesenteric artery to prevent interruption of blood flow. The kidney was removed and perfused with oxygenated Krebs' buffer at 37°C at constant flow to obtain a perfusion pressure of 60 to 85 mm Hg. Once a stable perfusion pressure was obtained, vasoconstrictor responses to AA (1 and 3 µg), which are mediated by endoperoxides, and phenylephrine (100 ng) were determined. Two-minute collections of the combined venous and ureteral perfusate were made for determination of PGE2 and 6-ketoPGF1 immediately before and after administration of AA (1 µg). The left kidney was removed for determination of renal cortical COX-2 and nitrotyrosine protein expression. Glucose levels in tail vein blood were determined with a glucometer (Ames, Elkhart, IN).
Prostaglandin and Isoprostane Measurements. Two-minute perfusate collections were made immediately before and after the administration of 1 µg of AA for the measurements of PGE2 and 6-ketoPGF1 as indices 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, the hydrolysis product of prostacyclin, 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. Thromboxane levels were not determined in these experiments because we have previously shown that they are lower than the levels of PGE2 and 6-ketoPGF1 and do not contribute to the renal vaso-constrictor effect of AA (Quilley et al., 1989). Twenty-four hour urine samples were obtained from rats placed in metabolic cages, and 8-isoprostane PGF2 levels were measured by enzyme immunoassay using a kit from Cayman Chemical.
Creatinine Clearance. Creatinine was measured in urine and plasma samples by the Jaffe method using reagents from Thermo DMA (Arlington, TX), and GFR was calculated using standard formulae.
Western Blot for COX-2 and Nitrotyrosine Expression. The cortex was homogenized in radioimmunoprecipitation assay buffer and subjected to three 15-min periods of centrifugation at 14,000 rpm. The protein in the supernatant was determined using a Bio-Rad assay kit (Bio-Rad, Hercules, CA) and was mixed with 2x SDS-polyacrylamide gel electrophoresis sample buffer (500 mM dithiothreitol, 0.2% bromophenol blue, and 50% glycerol) and boiled for 4 min. Twenty-five micrograms of protein from each sample was loaded and separated on a 10% SDS-polyacrylamide gel electrophoresis gel, transferred to a polyvinylidene difluoride membrane, and immunoblotted with either a rabbit anti-mouse COX-2 polyclonal antibody (1:1000 dilution; Cayman Chemical) or a biotinylated nitrotyrosine monoclonal antibody (1:5000; Cayman Chemical). Membranes were washed with Tris-buffered saline containing Tween 20 and incubated with IRDye (Rockland, Gilbertsville, PA). The immunopositive bands were visualized with infrared fluorescence (Odyssey; LI-COR, Lincoln, NE).
Analysis of Data. All data are expressed as means ± S.E.M. and were compared using an unpaired Student's t test or analysis of variance in which individual points were compared using a modified t statistic (Bonferroni). p < 0.05 was considered statistically significant.
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Results |
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Isolated Perfused Kidney. Basal perfusion pressures in the control, diabetic, fenofibrate-treated control and fenofibrate-treated diabetic groups were 74 ± 7, 69 ± 3, 74 ± 4, and 72 ± 3 mm Hg, respectively, and perfusate flow rates were 9.6 ± 0.7, 16.4 ± 2.5, 9.1 ± 1.6, and 9.1 ± 0.3 ml/min, respectively. Figure 1 shows the vasoconstrictor responses to AA and phenylephrine in the various groups. The increase in perfusion pressure in response to AA was much greater in the untreated diabetic group compared with the untreated control group. Fenofibrate treatment did not affect the vasoconstrictor response to AA in the nondiabetic group but reduced the response in diabetic rats, especially that of the 1 µg dose of AA. Vasoconstrictor responses to phenylephrine were not different between untreated diabetic and control rats, but fenofibrate treatment tended to reduce the response in both diabetic and nondiabetic rats (Fig. 1).
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Release of Prostaglandins. As we have reported before, the enhanced endoperoxide-mediated vasoconstrictor response to AA in the diabetic rat kidney was accompanied by an exaggerated release of prostaglandins. Both 6-ketoPGF1, and PGE2 release from diabetic rat kidneys in response to AA were markedly enhanced compared with control rat kidneys (Figs. 2 and 3). The enhanced release of 6-ketoPGF1 was prevented by treatment of diabetic rats with fenofibrate, which did not affect basal release in either control or diabetic rats. In contrast to 6-ketoPGF1, basal release of PGE2 was less from diabetic rat kidneys compared with control and fenofibrate reduced basal release in the nondiabetic rats. The enhanced renal release of PGE2 in response to AA in the diabetic rat was completely prevented by fenofibrate treatment, which also reduced AA-stimulated release in nondiabetic rats.
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Isoprostane Excretion. Urinary isoprostane excretion was increased approximately 2-fold in untreated diabetic rats compared with controls as we have previously reported (Li et al., 2005) and was unaffected by fenofibrate treatment in either control or diabetic rats.
Cyclooxygenase Expression. Figure 5 show a Western blot for renal cortical COX-2 expression in control and diabetic rats and the effects of fenofibrate treatment. The blot (upper panel) indicates that COX-2 expression is increased in the diabetic rat compared with control; this was confirmed by estimation of the relative density (lower panel), although the increase was not as great as we have observed in previous studies. Fenofibrate treatment had little effect on renal COX-2 expression in nondiabetic rats but reduced that of diabetic rats, so there was no difference from control rats.
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Discussion |
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). We also confirmed an increase in nitrosative stress by showing increased expression of nitrotyrosine, a marker for peroxynitrite. In the current study, we show that fenofibrate treatment of diabetic rats prevents the above manifestations of diabetes and, in addition, moderates the characteristic increase in GFR.
The increase in renal COX-2 in diabetes has been attributed to hyperglycemia-induced oxidative stress, and we have reported that treatment of diabetic rats with Tempol to reduce superoxide prevents the increase in renal COX-2 expression and the associated increase in the release of AA-stimulated prostaglandin release from the perfused kidney (Li et al., 2005). Because treatment of diabetic rats with N-nitro-L-arginine methyl ester to inhibit NO formation produced similar effects as Tempol, we suggested that peroxynitrite might be the stimulus for the induction of renal COX-2 (Chen et al., 2006). This idea receives support from the results of the present study where there is an association between COX-2 expression and nitrotyrosine expression, both of which are increased in the kidney of the diabetic rat. Moreover, fenofibrate treatment of diabetic rats prevented the increased renal expression of COX-2, which was associated with a reduction of peroxynitrite generation using nitrotyrosine expression as a marker. The source of NO for the reaction with superoxide to form peroxynitrite in the diabetic rat kidney is not known, and there have been variable reports of the renal expression of NOS isoforms in diabetes. Thus, Cosenzi et al. (2002) found increased iNOS in the kidney of diabetic rats, and iNOS expression was increased in endothelial cells exposed to high glucose (Rodriguez et al., 2006). In contrast, Veelken et al. (2000) reported increased endothelial NOS in glomeruli from diabetic rats, and Ito et al. (2001) reported increased renal neuronal NOS mRNA. Similarly, there are several potential sources of superoxide in diabetes including the mitochondrial electron chain. Thus, Nishikawa et al. (2000) reported that normalizing mitochondrial superoxide formation in endothelial cells exposed to elevated glucose prevented activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation, and activation of NFB. However, the increase in oxidative stress in diabetes has been attributed to increased activity of NADPH oxidase, which is associated with increased expression of NOX4 and p22phox subunits in the kidney (Etoh et al., 2003) and gp91phox subunit in the mesenteric vasculature (Ding et al., 2007) and aorta (Kanie et al., 2003). The increase in gp91phox was associated with reduced aortic expression of mRNA for PPAR in the diabetic rat and could be reduced by bezafibrate treatment, providing a link between PPAR and oxidative stress (Kanie et al., 2003). Indeed, bezafibrate has been reported to decrease mRNA for NADPH oxidase in cultured human and umbilical vein endothelial cells (Inoue et al., 2001) and to increase mRNA for superoxide dismutase in the liver (Inoue et al., 1998). We have not addressed expression of NADPH oxidase or superoxide dismutase in the kidney as a mechanism for the effect of fenofibrate in preventing the up-regulation of COX-2 in the diabetic rat, but, based on our earlier results with Tempol, a reduction in oxidative stress in response to PPAR activation should prevent the increase in COX-2. However, we found that fenofibrate treatment did not reduce urinary isoprostane excretion that was increased in the diabetic rat and is used as an index of oxidative stress. This suggests that fenofibrate may not simply be acting to reduce oxidative stress, although it is clear that fenofibrate treatment reduced the expression of renal nitrotyrosine expression in the diabetic rat, which raises the possibility that fenofibrate might reduce the formation of NO to generate peroxynitrite. This could relate to an effect of fenofibrate to inhibit activation of NFB, which is an obligatory step in the induction of iNOS. Thus, fenofibrate has been reported to increase IB to inhibit NFB (Cernuda-Morollón et al., 2002). The results of the present study do not delineate the sequence of events in which fenofibrate prevents the up-regulation of COX-2 in the diabetic rat but point to the likelihood that it relates to a reduction of nitrosative stress. Thus, fenofibrate treatment did not affect blood glucose levels in the diabetic rat but did reduce the generation of peroxynitrite. However, we cannot exclude an effect of fenofibrate to prevent the increase in oxidative stress that is associated with diabetes, despite the isoprostane results. Thus, hyperglycemia has been shown to increase oxidative stress (Catherwood et al., 2002; Cosentino et al., 2003), which has been shown to increase COX-2 expression in a variety of cultured cell types (Cosentino et al., 2003; Kiritoshi et al., 2003). Our study with Tempol provided direct evidence of the link between oxidative stress and the induction of COX-2 in diabetes, and fenofibrate has been reported to reduce oxidative stress (Inoue et al., 2001). Nonetheless, we cannot exclude a role of IB to inhibit NFB in the effect of fenofibrate to reduce expression of COX-2 in the diabetic rat.
Coincident with the effect to reduce nitrosative stress and to prevent the increase in renal COX-2 expression, fenofibrate treatment moderated the increase in GFR in the diabetic rat. We used creatinine clearance to estimate GFR (Zager, 1987; Palm and Lundblad, 2005), and the value we obtained for rats was well within the range of that reported by other investigators using alternate methods. The untreated diabetic rats exhibited hyperfiltration compared with control rats, and treatment with fenofibrate resulted in a GFR between control and untreated diabetic rats. Because renal COX-2 expression has been linked to hyperfiltration in diabetes, it is tempting to speculate that fenofibrate limits the increase in GFR by preventing the increase in COX-2. Thus, inhibition of COX-2 was shown to reduce GFR in the STZ-diabetic rat and to reduce the appearance of markers of renal damage in a hypertensive diabetic rat model (Cheng et al., 2002). Moreover, a recent study showed that fenofibrate treatment improved diabetic nephropathy in db/db mice (Park et al., 2006). However, in this type 2 diabetic model, fenofibrate greatly improved hyperglycemia, whereas in our STZ model, fenofibrate had no effect on blood glucose levels. This suggests that the beneficial effects of fenofibrate in the two diabetic models may involve different mechanisms, although oxidative stress has been associated with insulin resistance, and reducing oxidative stress has been reported to increase insulin sensitivity.
Despite moderating the increase in GFR, which has also been linked to renal hypertrophy, fenofibrate did not reduce kidney size compared with untreated diabetic rats. In fact, if kidney weight/body weight ratio was used, fenofibrate resulted in a greater increase than that seen with the untreated diabetic group. This is not surprising when considering that fenofibrate activates nuclear receptors that increase DNA transcription and protein synthesis. Similarly, in nondiabetic rats, fenofibrate increased the kidney weight/body weight ratio compared with untreated rats, which has been reported for Fischer rats (Klinger et al., 1998). In our study, both control and diabetic rats treated with fenofibrate exhibited less weight gain compared with their untreated counterparts, which has also been reported and contributes to the increased kidney weight/body weight ratio.
In summary, we report that fenofibrate treatment of the STZ-diabetic rat reduces nitrosative stress using nitrotyrosine expression as an index, and this is associated with prevention of the up-regulation of renal COX-2 and a reduction in the degree of hyperfiltration. The observation that fenofibrate reduced peroxynitrite generation may be of great significance because more and more studies implicate peroxynitrite in the development of complications of diabetes (Pacher et al., 2007); reducing peroxynitrite should be beneficial, especially when coupled with the effects of fenofibrate to reduce hyperlipidemia in patients with metabolic syndrome (Rosenson et al., 2007).
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Acknowledgements |
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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; NOS, nitric-oxide synthase; PPAR, peroxisome proliferator-activated receptor; NF, nuclear factor; PG, prostaglandin; iNOS, inducible nitric-oxide synthase.
Address correspondence to: John Quilley, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail: john_quilley{at}nymc.edu
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